- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Annual Issues
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Reviewers Acknowledgment
- Submit a Manuscript
- Subscription Information
- Table of Contents
Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 836485, 32 pages
The Effects of TLR Activation on T-Cell Development and Differentiation
1Department of Gastroenterology, The 309th Hospital of The People's Liberation Army, Beijing 100091, China
2Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
3Savient Pharmaceuticals, East Brunswick, NJ 08116, USA
Received 14 November 2011; Accepted 26 January 2012
Academic Editor: Ana Lepique
Copyright © 2012 Bo Jin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.
Innate immunity protects the host from pathogenic infectious agents. Every infectious microorganism possesses conserved molecular structures, for example, lipopolysaccharide, peptidoglycan, flagellin, microbial nucleic acids and these are collectively referred to as pathogen-associated molecular patterns (PAMPs) . PAMPs are recognized by corresponding germline-encoded pattern recognition receptor (PRR) expressed on innate immune cells of the host, for example, dendritic cells (DCs), macrophages and neutrophils [2, 3]. This triggers various signal pathways to produce inflammatory responses and adaptive immunity [4, 5].
At least 5 classes of PRRs have been characterized: Toll-like receptors (TLRs), retinoic-acid-inducible gene-I- (RIG-I-) like receptors (RLRs), nucleotide-binding domain and leucine-rich repeat containing gene family (alternatively named NOD-like receptors, NLRs), C-type lectin receptors (CLRs) and cytosolic DNA receptors (CDRs) [4, 6]. TLRs are membrane-bound receptors that sense PAMPs on the cell surface or in endosomes , while RLRs and NLRs recognize microbial molecules in the host cytosol . CLRs are primarily expressed in myeloid cells and recognize polysaccharide structures of pathogens inducing immune responses [6, 9]. With the exception of TLR9, CDRs are a new family composed of at least 6 members that also trigger innate immunity upon detecting cytosolic DNA [10, 11]. TLRs were initially discovered in 1997  and represent a canonical family of PRRs that govern adaptive immune response by inducing a Th1-skewed response, immunoglobulin G2c production and antigen-specific cytotoxic T lymphocyte (CTL) response [13–15].
Upon recognition of foreign antigen for DCs via the TLR-PAMP interaction [4, 16], immature DCs resident in tissues mature into professional antigen-presenting cells (APCs) to induce effector and memory T-cell responses in lymphoid organs. Additionally, DCs are capable of inducing antigen-specific T-cell tolerance immunosuppression (Figure 1) . T cells are divided into different subsets based on their phenotypes, intracellular molecules expression, cytokine production, the lengths of telomeres and state of immunity . The current knowledge of TLRs activation in relation to T-cell activation and differentiation is presented here.
2. T Lymphocyte Development and Subsets Differentiation
2.1. T-Cell Development in Thymus (Figure 2)
Thymic T-cell progenitors are believed to come from circulating hematopoietic stem cells originating from bone marrow. All peripheral T cells are developed from these progenitor cells [18–20]. The entry of T-lymphoid progenitor cells at an early embryonic developmental stage before vascularization of thymus, or at later embryonic and postnatal stages after vascularization, initiates development of T cells in the thymus [21, 22]. Thus, T progenitor cells can travel to and reside in thymus via either a nonvascular route at an early embryonic developmental stage or via a vascular way at late embryonic and postnatal stages. Chemokines such as C-C chemokine receptor type 7 (CCR7) and CCR9 play a role in the prevascular colonization of T-cell progenitors into the thymus primordium , while the combination of P-selectin and P-selectin glycoprotein ligand-1 is involved in postnatal thymus seeding . These cells initially express neither CD4 nor CD8 and are referred to CD4/CD8 double-negative (DN) thymocytes . Such DN thymocytes migrate from the corticomedullary junction to the subcapsular region of the cortex and sequentially transform into DN1 (CD44+CD25−), DN2 (CD44+CD25+), DN3 (CD44−CD25+) and DN4 (CD44−CD25−) [25–27] cells with weak expression of CD4, CD8, CD25 and CD44. These are the direct precursors of CD4/CD8 double-positive (DP) thymocytes . DP thymocytes develop in thymus cortex from pre-DP where son of sevenless gene 1 (Sos1), a guanine nucleotide exchange factor for Ras, plays a pivotal role during this transition . DP thymocytes express TCRαβ on the cell surface and these interact with self-peptide-MHC complexes presented by cortical thymic epithelial cells (cTECs) for positive selection (i.e., survival) or negative selection (clonal deletion, i.e. death). The process is determined by avidity and aggregation of TCR with the ligand interacting with one another . Development of single positive (SP) lineages of CD4+CD8− or CD4−CD8+ thymocytes is determined during positive selection  and the properties of protein degradation and self-peptide presentation of cTEC may play a role in SP lineages positive selection [30, 31].
Positively selected thymocytes migrate to the medulla via CCR7-mediated chemotaxis . The medullary TECs (mTEC) ectopically express multifarious “tissue-specific” antigens (TSAs)/peripheral tissue-restricted antigens (PTAs), that is, promiscuous gene expression representing peripheral tissues [32, 33]. This expression is partially controlled by the transcription factor autoimmune regulator (AIRE) . Antigens from either apoptotic mature mTECs or peripheral tissues are taken up by thymic DCs and cross-presented to developing thymocytes to induce negative selection of self-reactive thymocytes establishing self-tolerance . It is suggested that circulating DCs bearing peripheral tissue antigens are also recruited intrathymically for cross-presentation and therefore involved in clonal deletion . Mature thymocytes that have completed T-cell development emigrate from thymus through perivascular space in the corticomedullary junction and medulla  to peripheral lymphoid organs. T-cell emigration is regulated by sphingosine-1-phosphate receptor 1 [37, 38]. Different subsets of T cells may have different affinities for blood/lymphatic vessels and these determine the routes of emigration . A new subset phenotypically and functionally distinct from peripheral naive T cell that emigrates from the thymus referred to recent thymic emigrants (RTEs) requires further maturation in secondary lymphoid organ to become functionally competent peripheral T cells .
Self-tolerance is induced in thymus either by negative selection or by natural regulatory T cells (nTreg) development. Most of the nTreg cells are derived from CD4+ SP thymocytes residing in the medullary compartment of the thymus [40, 41]. It is hypothesized that tolerance of uncommon self-antigens such as myosin usually presents after muscle injury is preferentially recognized by TCR and mediated by nTreg cells. By contrast, cells that are involved in chronic engagement of TCR/CD28 signaling by recognizing ubiquitous antigen, for example, albumin, the 5th component of complement, insulin, are negatively selected [40, 42, 43]. Decreased presentation of cognate antigens on mTECs or DCs can induce nTreg cell development . Distinct APC subsets may preserve different TCR specificities and their ability to mediate negative selection [40, 45–47]. It has been suggested that forkhead box P3 (Foxp3) negative nTreg cell precursors, induced by TCR signaling, can use interleukin-2 (IL-2), IL-15, or IL-7 to activate Foxp3 expression without the need for additional TCR signals . It is believed that nTreg cell development begins early at the DP stage in pediatric thymus. Foxp3+ DP thymocytes with a functional IL-7 receptor and upregulated expression of Bcl-2 protect themselves from being negative selected. Foxp3+ DP thymocytes that express CD103 are possible precursor of Foxp3+ CD8+ SP cells . Hassall’s corpuscles, groups of epithelial cells in the thymic medulla, may serve as specialized small niches required to support nascent nTreg cell development .
2.2. Development of T-Cell Peripheral Tolerance (Figure 3)
In addition to the tolerance induced in thymus, autoreactive T cells that have escaped from negative selection in thymus due to low avidity of TCR to self-peptide-MHC complex  or insufficiently expressed TSA in mTECs will be deleted (cell death) or inactivated (anergy) in periphery, that is, peripheral tolerance .
Lymph nodes are a primary location where peripheral tolerance takes place. It has been demonstrated that lymph node stromal cells (LNSCs), similar to mTECs in thymus, are able to express a variety of TSAs to induce immune tolerance of T cells . The peripheral expression of TSAs is either AIRE dependent [52, 53] or independent . Another regulating factor, deformed epidermal autoregulatory factor 1 (Deaf1) is also involved in PTAs expression . Deaf1 variant isoforms inhibit the transcriptional activity of canonical Deaf1 and this suppresses PTA expression . Deaf1 transcript has been detected in every subset of LNSCs . All the subsets of LNSCs can express TSAs and present TSAs to activate antigen-specific CD8+ T cells under both steady-state and inflammatory conditions . By contrast, cross-presentation of TSAs produced from LNSCs by lymph node resident DCs does not seem to play an important role . Although TSA proteins expressed by LNSCs might be functional [51, 58], the expression of TSA protein by LNSCs is different from its expression in peripheral tissue. This is evidenced by the fact that even the products from a single type of differentiated peripheral cell can be produced separately from distinct subsets of LNSCs, for example, both the protein of mlana gene expression and tyrosinase are products of terminally differentiated melanocytes, their mRNA expression as PTAs in lymph node is segregated in fibroblastic reticular cells (FRCs)  and lymphatic endothelial cells (LECs) , respectively. In addition to TSAs expressed by LNSCs, lymph can also serve as a source of self-antigens to induce peripheral tolerance in lymph node . Compared with plasma, lymph contains more processed protein fragments and peptides from draining organs or tissues  and thus a significant pool of self-antigen for the induction of peripheral tolerance .
LNSCs are reported capable of upregulating co-stimulatory molecules to induce T-cell lineage deletion rather than activation . The role of LNSCs in the induction of Treg cell is unknown . It has been suggested that autoimmunity is promoted by induction of self-antigen specific effector-memory T cells when their TCR is continuously engaged at sites of high TSA expression under conditions of tissue injury, infection and/or inflammation . Without inflammation, DCs resident in peripheral lymph organs would induce tolerance in naive T cells bearing TCR with high avidity for self-antigen and incomplete maturation of DC also serves tolerance induction . The peripheral deletion of autoreactive T-cell lineage is mediated by an apoptosis involving activation of Fas receptor by Fas ligand and inactivation of survival protein B cell lymphoma 2 (Bcl-2) by its antagonist Bcl-2-interacting mediator of cell death (Bim) [42, 61]. A nonapoptotic mechanism of peripheral deletion was recently identified in which autoreactive CD8+ T cells actively invade hepatocytes in liver and are degraded in the endosome/lysosome of the hepatocytes . This process is known as emperipolesis  and has been described as early as the 1920s . The invasion of T cells into hepatocyte is dependent on T-cell activation, filamentous actin reorganization, myosin light chain kinase, as well as other kinases like PI3K. Inhibition of this suicide emperipolesis by wortmannin, a kinase inhibitor capable of inhibiting T-cell invasion into hepatocytes in vivo, is associated with accumulation of autoreactive CD8+ T cells in the liver, and breach of tolerance results in the development of autoimmune hepatitis . By interrupting costimulation, functional tolerance of T cell, that is, anergy can be developed and maintained by counter-regulatory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that shares structural similarity with CD28 capable of binding CD80 and CD86 and blocking CD28 costimulation [42, 65]. Another counter-regulatory molecule, programmed cell death-1 (PD-1) is also crucial for the maintenance of peripheral tolerance .
2.3. Development of Mucosal Tolerance
Mucosa discussed here are those that line the gastrointestinal system and the respiratory system including nasal passages. The largest immune organ of the body is the gut-associated lymphoid tissue (GALT) consisting of Peyer’s patches and isolated lymphoid follicles  located within the small intestine. Each meter of human intestine has approximately 1012 lymphoid cells . GALT processes dietary antigens and is responsible for immunotolerance toward intestinal commensal flora.
Intestinal commensal microbiota is essential for adaptive and innate immunity. In germ-free mice, the absence of these bacteria results in impaired local and systemic immune responses. This is evidenced by a reduced number and smaller sized Peyer’s patches, a reduced number of mesenteric lymph nodes and diminished IgA and IgG production [66, 68–70].
Metabolites of intestinal microbiota, for example, in mice with dextran-sulfate-sodium- (DSS-) induced colitis, short-chain fatty acids such as acetate, a fermented product of Bifidobacterium when it acts on dietary fiber, interact with G-protein-coupled receptor 43 and stop the differentiation of IL-17-producing cells in the lamina propria . Metabolites from food and food proteins also determine susceptibility to systemic infection, immunoreactivity and immune tolerance [72–75]. A unique property of mucosa when exposed to ingested antigens is suppression of immune responses to subsequent parenteral challenges with the same antigen [76, 77]. This physiologically induced tolerance is referred to as oral tolerance [66, 67, 78, 79]. Mucosal DCs can produce TGF-β, IL-10 and induce CD103+ DCs to promote Tregs induction [80, 81]. Resident lamina propria CD103+ DCs can promote Foxp3+ Treg cell differentiation and induce gut-homing receptors, for example, CCR9 and α4β7 integrin expression in T cells .
The orally ingested antigen can be taken up by a variety of mechanisms. Microfold cells (M cells) are specialized epithelial cells without microvilli and thick glycocalyx in the small intestine overlying Peyer’s patches and lymphoid follicles and are responsible for transcytosis . These cells express TLR4, platelet-activating factor receptor, α5β1 integrin and galectin-9 on cell surfaces that enable M cells to sense and transport intestinal antigens into intraepithelial pockets to be processed by APCs . Intestinal columnar epithelial cells are also capable of transporting luminal antigens through these PRRs  or the epithelial-associated neonatal Fc receptor to secrete and combine IgG or IgG-antigen complexes to cross mucosal epithelial cells . DCs by their cellular processes which traverse the epithelium without disrupting tight junctions can sense luminal antigens [85, 86].
A variety of regulatory mechanisms are involved in oral tolerance. The amount of ingested antigen is a major factor that determines the mechanism of oral tolerance. Generally, low amounts of antigen result in Treg induction while higher doses lead to immune cell anergy or clonal deletion . Activation of mesenteric lymph node CD103+ DCs preferentially induces Foxp3+ Treg cells differentiation from Foxp3− naive conventional CD4+ T cells in the presence of TGF-β and the dietary vitamin A metabolite, retinoic acid [81, 87]. CD103+ DCs express a retinal dehydrogenase, aldehyde dehydrogenase family 1 subfamily A2 that can convert retinal or vitamin A into retinoic acid. This facilitates Foxp3+ iTreg cell induction . Even in the absence of thymus-derived nTregs, the development of antigen-specific CD4+CD25+Foxp3+CD45RBlow cells that are anergic and suppressive can occur . Gut CD103+ DCs also expresses indoleamine 2, 3-dioxygenase (IDO) involved in the activation of Foxp3+ iTreg cells and hence oral tolerance . TGF-β can transform IDO− DCs into IDO+ DCs in mice and prostaglandin E2 plays similar role in human . This process involves intracellular signaling for the self-amplification and maintenance of a stable regulatory phenotype in pDCs .
All major types of regulatory T cells are involved in oral tolerance, including thymic-derived nTreg, mucosally induced iTreg, IL-10 secreting CD4+CD25lowCD45RBlow type 1 regulatory T cell (Tr1 cell), TGF-β-dependent latency-associated peptide (LAP)+ Th3 type Treg and CD8+ Treg . LAP is a propeptide capable of combining TGF-β to constitute a latent TGF-β complex . It has been suggested that after exposure of oral antigen, CD4+CD25−Foxp3−LAP+ Th3 cells produce TGF-β to support CD4+CD25+Foxp3+ nTreg cells, induce CD4+Foxp3− T-cells differentiation into Foxp3+CD25+LAP− iTreg cells and suppress Th1 and Th2 responses . iTreg cells may modulate DCs to produce IL-27 which induces IL-10-producing Tr1 cells . Foxp3+ iTreg cells are essential for mucosal tolerance development . Oral tolerance can also be elicited by oral administration of anti-CD3 monoclonal antibody instead of application of cognate antigen to activate TCR and induce Th3 type CD4+CD25−LAP+ Tregs in mesenteric lymph nodes . Oral exposure to ligands of aryl hydrocarbon receptor is also capable of inducing Foxp3+ Treg and Tr1 cells by acting on both T cells and DCs producing IL-27, retinoic acid and IL-10 in the gut [94, 95].
Nasal administration of antigen preferentially induces IL-10-dependent Treg cell development, for example, Tr1 cell and CD4+CD25−LAP+ Treg cell [67, 96, 97]. As the antigen exposed to respiratory mucosa does not exert digestion that occurred in the gut, the antigen dosage required to induce nasal tolerance is smaller than that needed in the induction of oral tolerance . DCs that produce IL-10 in the lungs are critical in the induction of IL-10-secreting Tr1 cell development which elicits nasal tolerance . The CD4+Foxp3+ Treg cells expressing membrane-bound TGF-β also participates in nasal tolerance . CCR7-dependent migration of CD103+ and CD103− pulmonary dendritic cells to the bronchial lymph node is indispensable for nasal tolerance induction . CD11b+ and CD103+ DCs are the major DC subsets in the lung. In contrast to the actions in the gut, pulmonary CD103+ DCs appears to prime Th2 responses to the inhaled antigen while CD11bhi DCs elicit Th1 responses .
2.4. T-Cell Subsets Development and Differentiation in Periphery (Figure 2)
CD4+ T cells play critical roles in the functioning of the host immune system. Upon stimulation, peripheral CD4+ T cells can differentiate into T helper (Th) cells or inducible Treg cells (iTreg). Currently, at least 4 Th cell subsets have been identified, Th1, Th2, Th17 and iTreg . T follicular helper (Tfh) has been suggested as a new subset of Th family [104–106]. There is debate whether new subsets such as Th9, Th22 [107–109] are separate lineages [103, 110].
APCs take up antigen and digest it in the cytosol to process the epitope. The epitope is then presented together with MHC molecules to TCR on the T-cell surface. Simultaneously, APCs also secrete co-stimulatory molecules for example, CD80, CD86 that bind the co-stimulatory receptor of T cells, for example, CD28. Thus all 3 elements are required for T-cell activation, that is, epitope, MHC molecules and costimulation signals. Upon TCR activation, T cells produce CD154 (alternatively named CD40L) to bind CD40 on the cell surface of APCs to further activate APCs. The lineage commitment of Th cells is determined by the cytokine milieu, transcription factors and co-stimulatory molecules such as CD28, CD154. The transcription factors involved in this process are activated by TCR signaling [16, 103]. IL-12  and interferon (IFN) γ  are essential for the induction of the Th1 cells. When cognate antigen stimulation is present, IL-4 and IL-2 are required by the naive CD4+ T cells to differentiate into IL-4-producing Th2 cells [113, 114]. Transforming growth factor- (TGF-) β stimulates naive CD4+ T cells either to differentiate into Th17 cells in the presence of IL-6 or alternatively differentiate into iTreg cells in the presence of IL-2 (or IL-1β in human) [115–117]. In the absence of IL-6 and in the presence of TGF-β and IL-21, Th17 cells can also be induced . Primed CD4+ T cells are also able to differentiate into Tfh cells in the presence of IL-6 (mice) or IL-12 (human) expressing IL-21 [119–122]. IL-21 can promote Tfh cell differentiation by feedback. Therefore, it has been proposed that major products of the differentiated cells, for example, IFN-γ from Th1, IL-4 from Th2, IL-17 from Th17, IL-21 from Tfh, play critical roles in its self-induction .
Newly primed CD4+ T cells are programmed by various cytokines and other factors from DCs to produce transcription factors. T box expressed in T cells (T-bet) is a major factor for Th1 cell differentiation and IFN-γ production . It can induce chromatin remodeling of IFN-γ alleles and IL-12 receptor (IL-12R) β2 expression and this promotes IFN-γ production as well as Th1 cell expansion induced by IL-12 . However, in mature Th1 cells, reiteration of IFN-γ expression and stable chromatin remodeling are relatively independent of T-bet activity . Signal transducer and activator of transcription (STAT) protein 4 and STAT1 are involved in Th1 cell differentiation. STAT4 is activated by IL-12 leading to Th1 and Th17 cells differentiation. IFN-γ production also occurs with nuclear factor κB (NF-κB) with multiple cis elements being involved [126, 127]. STAT1 can be activated by IFN-γ and serves as a regulator of T-bet activation and subsequent IL-12R expression in vitro . The role of IFN-γ/STAT1 autocrine pathway in CD4+ T-cell differentiation in vivo is not fully understood .
GATA3, a member of GATA transcription factor family capable of binding to the DNA sequence “GATA,” is the master regulator of Th2 . Without GATA3, Th2 cell differentiation is completely abolished both in vivo and in vitro [130, 131]. GATA3 can bind to 1279 genes in Th2 cells and 17 genes in 26 highly Th2-specific STAT6-dependent inducible genes. Among the 26 Th2-specific genes, 10 showed GATA3-dependent transcription while the remaining 16 genes were STAT6 dependent . Production of Th2 cytokines is also promoted by GATA3 binding to promoters of IL-5 , IL-13 , and enhancers of IL-4 . GATA3 has the ability to instruct Th2 commitment, promote Th2 cell expansion, suppress Th1 cell differentiation, thus facilitating Th2 differentiation .
STAT6 and STAT5 are essential in Th2 cell differentiation and expansion [136–139]. In vitro studies showed that activation of STAT6 is necessary and sufficient for Th2 cell differentiation with expansion triggered by IL-4 . However, Th2 lineage commitment can still be induced by activation of GATA3 in a STAT6-independent manner in vivo . Thus, it is possible that other transcription factors beside STAT6 may be involved in GATA3 activation. A recent report suggested that T-cell factor 1 (TCF-1) participated in GATA3 activation and promoted STAT6-independent IL-4-producing Th2 cell differentiation . However, TCF-1 expression can be suppressed by IL-4 mediated by STAT6. Thus, the fine-tuning mechanism of Th cell polarization has a multichannel pattern . STAT6 is also involved in the expression of Th2-specific cytokines, for example, IL-24 is mediated by the coordinate action of STAT6 and c-Jun transcription factors at the transcriptional level . Recently, it was reported that STAT3 cooperates with STAT6 in promoting Th2 cell development . A strong STAT5 signaling, correlated with higher expression of CD25, is required for Th2 and iTreg cell differentiation. By contrast, weak STAT5 signaling causes cell proliferation and survival of Th1 and Th17 cells . In vivo, promiscuous expression of an activated form of STAT5 suppresses the production of both Th1 and Th17 cytokines and promotes the development of Th2 lineage cells .
The master regulator of Th17 cell is retinoic acid receptor related orphan receptor-γt (ROR-γt) [146, 147]. ROR-γt deficiency results in significant reduction in IL-17 production. The residual IL-17 production in ROR-γt-deficient cells appears to be attributed to ROR-α. Dual deficiency of ROR-γt and ROR-α completely abolished IL-17 production . SR1001, a high-affinity synthetic ligand binding to the ligand-binding domains of both ROR-γt and ROR-α that induces a conformational change within the ligand-binding domain, is capable of reducing affinity for coactivators and increasing affinity for corepressors. This results in suppression of the receptors’ transcriptional activity. Blocking the activities of ROR-γt and ROR-α with SR1001 can inhibit Th17 cell differentiation and function and suppress cytokines expression in mature Th17 cells . STAT3 is involved in Th17 cell differentiation, expansion and maintenance [103, 149]. Stimulation of the common precursor cell of Treg/Th17 by IL-6 activates STAT3 signaling and induces IL-21 expression . IL-21 induces Th17 differentiation, suppresses Foxp3 expression and maintains a sustained STAT3 activation in a self-service autocrine pattern, that is, Th17 cells secrete IL-21, which in turn causes Th17 cells to induce cell differentiation . STAT3 can also be activated by IL-23 and is responsible for the induction of ROR-γt and IL-23R allowing the persistence of Th17 cells [103, 150, 152].
Treg cell development is controlled by the transcription factor Foxp3 [153, 154]. Mutation of Foxp3 gene results in fatal autoimmune disorders in human, for example, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome or in mice, for example, lymphoproliferative disorder and stable expression of Foxp3 is essential for immune homeostasis [155, 156]. Foxp3 is required for Treg lineage commitment, differentiation, expansion and function [153, 154, 157]. Sustained expression of Foxp3 in the mature Treg cell is essential to maintain the existing phenotype status and to execute the immunosuppressive function of Treg cell. Reduced or abolished Foxp3 production in Treg cells results in acquisition of effector T-cell properties to produce inflammatory cytokines [158–160]. Foxp3 is probably a major but not the master regulator of Treg cell  and indeed, it is not necessary for Treg cell development or functioning under certain conditions, for example, the lineage commitment of Treg cells in murine thymus does not require the expression of functional Foxp3 protein . Activated purified naive CD4+ T cells transduced with a retroviral vector encoding Foxp3 and a Thy1.1 reporter produce a >95% Foxp3+ cell population but reproduce only a fraction of the Treg cell signature transcript . Instead, other transcriptional regulators, for example, the combination of IL-2–STAT5 signaling and TGF-β or CD103 responding to Foxp3 play complementary and synergistic roles in controlling Treg cell signature gene expression . Cytokines such as IL-2, TGF-β induce Foxp3 expression and also activate STAT5. The latter directly binds the promoter and the first intron of Foxp3 gene to promote Treg cell development. The loss of STAT5 activation abolished Treg cell differentiation [164–168]. However, Foxp3 can be induced in the absence of STAT5 in developing thymocytes, and the maintenance of Foxp3 expression in Treg cells is STAT5 independent . Perhaps cytokine-induced STAT5 activation is not required in the development of CD4+CD25+CD122+GITRhiFoxp3− Treg cell progenitor. Nevertheless, activated STAT5 plays a critical role in converting Treg cell progenitors into mature Treg cells [40, 137, 169]. Treg cell suppresses Th1 cell function through inhibition of IFN-γ transcription during Th1 priming without disrupting T-bet expression and Th1 programming. This suppression is either IL-10 dependent or independent depending on the target T-cell stage of activation and its tissue location .
Lineage commitment of Tfh cells is controlled by transcriptional factor Bcl-6, identified by the transcriptional profiles obtained from microarray analysis in Tfh cells that was Bcl-6 upregulated . Bcl-6-deficient T cells were unable to differentiate into Tfh cells and could not sustain germinal center responses [172, 173]. Enhanced expression of Bcl-6 in CD4+ T cells promoted expression of Tfh cell signature molecules CXCR5, CXCR4, PD-1, and downregulated IFN-γ and IL-17 production  inhibited other Th lineage cell differentiation . A transcriptional repressor, B lymphocyte-induced maturation protein 1 (Blimp-1) inhibits Tfh cell generation and function, indicating reciprocal regulation of Bcl-6 and Blimp-1 during Tfh cell differentiation . STAT3 is necessary for Tfh cell development [104, 175]. Deletion of STAT3 in CD4+ thymocytes resulted in a greatly reduced number of differentiated Tfh cells after immunization. STAT3 deficiency in T cells also led to defective germinal-center B cell generation and antibodies production [104, 175]. Without STAT3, for example, blockage by a STAT3 inhibitor, even after being activated by IL-6, Tfh cells did not signal B cells [175, 176].
When exposed to foreign antigens, peripheral naive CD8+ T cells differentiate into two reciprocal subsets: short-lived effector T cells, that is, CTLs and long-lived memory T cells [177–179]. Memory T cells can be subdivided into central (Tcm) or effector memory T cells (Tem). Tcm cells express high levels of CCR7 and CD62L and lack immediate effector function but efficiently stimulate DCs in secondary lymphoid organs inducing a new wave of effector cells when secondary challenge occurs. Tem cells express low levels of CCR7 and CD62L, migrate to the infection site and produce cytokines and cytolytic molecules [177, 180]. Tem cells possess most features of CTL. However, Tem cells persist after the elimination of the invading pathogen . A new memory T-cell subset with stem-cell-like properties has recently been identified and termed memory stem T cell (Tscm). This cell is present in humans  and mice . Phenotypically within the naive T-cell compartment, for example, CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+and IL-7Rα+, human Tscm cells highly express CD95, CXCR3, Bcl-2, the β chain of the IL-2 and IL-15 receptor (IL-2Rβ) and lymphocyte function-associated antigen 1 (LFA-1). These cells possess the characteristics of memory T cells such as the ability to rapidly acquire effector functions upon antigen rechallenge. They also can secrete inflammatory cytokines in response to α-CD3/CD2/CD28 stimulation. Such Tscm cells represent the least differentiated T memory cell subset . Wnt/β-catenin signaling may play a role in the induction of this subset  but there is conflicting evidence .
It has been suggested that the CD8+ effector and memory T cell develops from a single precursor cell when instructed by distinct TCR signals, cytokines [185–189] and not by the APC or when priming of T cell takes place . Naive CD8+ T cells when primed by signals from TCR and co-stimulatory molecules differentiate into precursor cells or early effector cells expressing transcription factor T-bet and cytotoxic cytokines, for example, IFN-γ, tumor necrosis factor (TNF) α to acquire partial cytolytic abilities . Whether the precursor cell further differentiates into late effector cell or memory cell is determined by a variety of factors such as the amount of IL-2R and IL-12 [190, 191], varying amounts of intracellular components, for example, T-bet, CD8, CD69, CD43, CD25, CD44, different expression of IFN-γ, Granzyme B, IL-7Rα, and distinct granularity due to asymmetric division [187, 192]. Point mutations in the TCR β transmembrane domain block the development and function of CD8+ memory T cells. Yet primary effector CD8+ T-cell response is not affected by this mutation. Mutant T cells are unable to induce polarized TCR and intact NF-κB signals in the immunological synapse (the interface between an APC and a lymphocyte). Therefore, distinct TCR signals trigger different programs for CD8+ T-cell differentiation toward either effector or memory pathways .
Transcriptional factors, T-bet, eomesodermin (Eomes), Bcl-6 and Blimp-1 are involved in CD8+ T-cell differentiation. T-bet is the master regulator of CD8+ T cells . Its expression is responsible for IFN-γ production and it participates in the activation of cytolytic genes, for example, Granyeme B, Perforin expression of CD8+ T cell . The presence of T-bet with a low level of IL-2 signaling is sufficient to induce CD8+ T cells to develop effector functions but other factors may also participate in terminal differentiation [194, 195]. Eomes, another member of the T-box family of transcriptional factors, is a key transcriptional factor for CD8+ T-cell differentiation . T-bet and Eomes cooperate redundantly to induce effector CD8+ T-cell differentiation and can also act reciprocally to induce memory CD8+ T-cell development . T-bet promotes the differentiation of short-lived effector CD8+ T cells at the expense of central memory cells and Eomes expression favors memory CD8+ T-cells differentiation [198, 199]. The differing quantities of T-bet in diverse T-cell lineages may be attributed to the asymmetric degradation . Proteasomes are unequally distributed during asymmetric cell division and this is responsible for the imbalanced degradation of T-bet in the daughter cells resulting in differing allocation of T-bet to various cell lines .
Bcl-6 and Blimp-1 are transcriptional repressors. Blimp-1 expression is required for the terminal differentiation of effector CD8+ T cells, that is, the short-lived CD8+ CTLs [200–202]. Bcl-6 probably works as a reciprocal regulator of Blimp-1 in the process of CD8+ T-cell differentiation . In general, lymphocytes with higher expression of Bcl-6 exhibit greater proliferative capacity, less secretory capacity and promote memory T-cell development. Lymphocytes with higher expression of Blimp-1 exhibit lower proliferative capacity and greater secretory capacity and they are more conducive to CTL development . Blimp-1 is also highly expressed in exhausted CD8+ T cells . T-bet can induce Blimp-1 transcription via enhanced IL-2R signaling .
STAT5 plays a critical role in the maintenance of phenotype of effector CD8+ T cells. It is also required in the induction of the anti-apoptotic molecule Bcl-2 expression by IL-7 and IL-15 and the maintenance of Bcl-2 expression in effector CD8+ T cells . Constitutive STAT5 activation can promote effector and memory CD8+ T-cell survival and Bcl-2 expression .
3. TLRs Signaling
3.1. The TLR Family
Toll was initially identified as an essential protein that plays a central role in the establishment of dorsoventral polarity in the embryo of Drosophila [207, 208]. Later, it was recognized as a key modulator for the immune response against fungi in adult Drosophila . Toll-receptor homologues have also been found to be capable of activating adaptive immune response through NF-κB signal [12, 210]. As these receptors are evolutionally and functionally homologous with Drosophila Toll, collectively they are referred to as Toll-like receptors [210, 211].
Thirteen TLRs have been currently identified, TLR1 to TLR13, of which TLR1 to TLR9 are conserved both in human and mice. TLR10 is not functional in mice while TLR11, TLR12 and TLR13 are absent from human genome . TLRs are type-1 transmembrane glycoproteins with a trimodular structure consisting of an N-terminal extracellular ectodomain characterized by inclusion of 16–28 leucine-rich repeats (LRRs), a transmembrane portion containing a single α-helix and an intracellular cytoplasmic portion with Toll/IL-1 receptor (TIR) domain [213, 214]. Each LRR region is composed of 24 amino acids with the conserved motif XLXXLXXLXLXXNXLXXLPXXXFX in sequence, an α-helix and a β-sheet connected by a loop in conformation [214, 215]. The LRRs of the ectodomain combine to display horseshoe-like shape. However, the LRR regions of TLR1, TLR2 and TLR4 do not have the typical conformation in that the conserved asparagine ladder in the central region of LRRs is absent. Consequently, this allows them to adjust their conformation to bind a variety of ligands and coreceptors for signaling . The TIR domain is composed of a five-stranded β-sheet encircled by 5 α-helices. The B-B loop that connects β-strand B with α-helix B in the TIR domain is considered the essential structure for TIR dimerization and subsequent recruitment of TIR domain-containing adaptors .
TLRs can be classified as cell-surface TLRs or intracellular TLRs. The former group consists of TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, TLR11 and TLR12, and it is largely expressed on the cell surface and recognizes molecules mainly from microbial membrane, for example, lipid, lipoprotein, or lipopeptide and protein. The latter group is composed of TLR3, TLR7, TLR8, TLR9, and perhaps TLR13 in mice localized in intracellular compartments like endoplasmic reticulum (ER), endosomes, lysosomes, and endolysosomes to detect microbial nucleic acids [212, 216]. The distinct ligand-sensing functions of the individual TLRs may explain their different localization. TLRs on cell surfaces mainly recognize molecules on the surface of the pathogenic microorganisms while those localized intracellularly sense nucleic acids which are released by intracellular degradation of the invading pathogen . An advantage of the intracellular localization of nucleic-acid-sensing TLRs may be the avoidance of TLRs activation by the host homogeneous nucleic acid. Such nucleic acids released from the dying cells can be readily degraded by serum or cytoplasmic nucleotidases before their arrival to the endosome. As nucleic acid-sensing TLRs reside intracellularly, this prevents the occurrence of autoimmunity. However, viral nucleic acid is protected by the viral capsid proteins and is capable of staying in the endolysosome, being recognized by nucleic-acid-sensing TLRs to trigger antiviral immunity [217, 218].
3.2. TLR Signaling Pathway
Intracellular TLRs are present in the ER in resting cells and move to endosomes upon stimulation of the cells (Figure 4). Their residence in ER is maintained by retention signals, for example, the cytoplasmic and ectodomains of TLR9 , a 23-amino acid sequence [Glu(727) to Asp(749)] present in the linker region between the transmembrane domain and TIR domain of TLR3 and the transmembrane region of TLR7 . These TLRs can only be activated after being transported to endolysosome . The trafficking of intracellular TLR9 from ER to endolysosomes is through traditional secretory pathways, and Golgi export is required for optimal TLR9 signaling [218, 221, 222]. Trafficking of TLR9 and TLR7 involves a cleavage by lysosomal cysteine proteases within their ectodomains. Without proteolytic modification, their association with myeloid differentiation protein 88 (MyD88) and subsequent signaling is disabled although the capacity of ligand-binding is preserved [216, 218, 221]. Proteolysis is not required for TLR3 signaling during its intracellular trafficking.
Chaperone proteins are required for maintaining the retention of these TLRs in ER in resting cells and their intracellular trafficking. UNC93B1, a highly conserved multiple membrane-spanning protein in ER, is involved in trafficking of nucleotide-sensing TLRs (Figure 4) . A point mutation of UNC93B1 abolishes signaling of TLR3, 7, 9 and 13 as binding to their transmembrane domains is prevented . Association with UNC93B1 promotes TLR9 signaling and represses TLR7-mediated response and mutation of the N-terminal D34A amino acid that suppresses TLR7 signaling enhances TLR7 trafficking and downregulates TLR9 trafficking in DCs. This suggests UNC93B1 favors DNA sensing but not RNA sensing. TLR3 signaling is promoted by overexpression of UNC93B1 and not affected by the N-terminal mutation . However, a recessive N-ethyl-N-nitrosourea-induced mutation (triple D or 3d mutation) that is a missense allele of UNC93B1 disrupts exogenous antigen presentation and signaling via TLR3, TLR7 and TLR9 . Therefore, UNC93B1 is essential for intracellular TLRs signaling and determines the trafficking efficiency of each individual TLR from ER to endolysosome to recognize the ligand and trigger subsequent response .
Upon binding ligands, TLRs dimerize to form homodimer or heterodimer (e.g., TLR2/TLR1, TLR2/TLR6 and perhaps TLR2/TLR10) and recruit adaptor molecules through the interaction of their intracellular TIR domain and the TIR domain of adaptor molecules . Four adaptor molecules have been characterized. MyD88  and TIR domain-containing adaptor inducing interferon-β (TRIF)/TIR domain containing adaptor molecule-1 (TICAM-1) [229, 230] are the two major adaptors for TLRs signaling. The remaining two adaptors, that is, TIR domain-containing adapter protein (TIRAP)/MyD88-adapter-like (Mal) [231, 232] and TRIF-related adaptor molecule (TRAM) , bridge the TIR domains between some TLRs and MyD88 or TRIF, respectively. MyD88 is a universal adaptor for all TLRs except for TLR3 and activates NF-κB signal pathway to induce inflammatory cytokines. TLR3 and TLR4 use TRIF as their adaptor to activate interferon regulatory factor 3 (IRF3) and NF-κB to promote the productions of type-I IFN and inflammatory cytokines. TIRAP/Mal is required for TLR4 and TLR2 signal transduction by bridging the TIR domain of TLR4 or TLR2 and MyD88 [215, 234]. Similarly, TRAM also acts as a bridging adaptor for TLR4 and TRIF .
MyD88 is the essential adaptor for most TLRs. Upon ligand recognition, TLR recruits MyD88 to its cytoplasmic TIR domain by association with the TIR domain of the adaptor molecule (Figure 5). MyD88 possesses an N-terminal death domain (DD) that associates with DD of IL-1R-associated kinase-4 (IRAK4) . IRAK1 and IRAK2 are phosphorylated by IRAK4 and then activate TNF receptor associated factor-6 (TRAF6) [236, 237]. TRAF6 acts as an E3 ubiquitin protein ligase to ubiquitinate itself and NF-κB essential modulator (NEMO) by the formation of polyubiquitin chains. Both TRAF6 and NEMO are connected with IRAK1 by the chains. These chains also connect NEMO with the transforming growth factor β-activated kinase-1- (TAK1-) binding proteins (TABs) including TAB2, 3 and 4 which promote phosphorylation of TAK1-TAB1 resulting in TAK1 activation [238–241]. The activated TAK1 induces phosphorylation of IκB kinase-related kinase (IKK) β. This causes IκB phosphorylation and its dissociation with NF-κB. Consequently, the nuclear translocation of NF-κB is induced and this culminates in the transcription of proinflammatory cytokines, for example, TNF and IL-6. The TAK1/TABs complex also phosphorylates and activates c-Jun N-terminal kinase (JNK) and p38 resulting in activation of activator protein 1 (AP1) [216, 227]. IRF5 can be activated by both MyD88 and TRAF6, and it promotes the transcription of proinflammatory cytokines . This can be inhibited by the competition by IRF4 . TRAF6 also induces TRAF3 triggering noncanonical TRAF3 self-ubiquitination  and this complex associates with TRAF family-member-associated NF-κB activator-binding kinase 1 (TBK1). It then acts with IRF3 to induce IFN-β production. Ubiquitinated TRAF3 also induces the anti-inflammatory cytokine IL-10 [245, 246]. In plasmacytoid DCs (pDCs), MyD88 signaling elicited by TLR7 and TLR9 is different from that in myeloid DCs (mDCs). Through phosphatidylinositol 3-kinase (PI3K), MyD88 signaling in pDCs ultimately activates IRF7 to induce production of enormous quantities of IFN-α [247–249]. In humans, TLR3 is predominantly expressed in mDCs whereas TLR7 and TLR9 are exclusively expressed in pDCs [250–255]. TLR expressions in murine DCs are not restricted as seen in human DCs. In mice, mDCs (alternatively named conventional DCs, cDCs) express all TLRs except TLR7 which is not expressed by CD8α+ mDCs [250, 256]. Indeed, murine pDCs highly express TLR7 and TLR9 along with mRNAs of all the remaining identified TLRs. TLR3 is preferentially expressed in CD8α+ mDCs and possibly not expressed in pDCs [250, 256]. Therefore, effective antitumor immunity elicited by CpG DNA in mouse is not seen in humans .
TRIF is the sole adaptor of TLR3 and the adjunctive adaptor of TLR4. After sensing dsRNA, the TIR domain of TLR3 associates TRIF TIR, then TRIF interacts with receptor-interacting protein 1 (RIP1) through the RIP homotypic interaction motif (RHIM) present in both proteins (Figure 6). TRAF6 is also recruited to the N-terminal domain of TRIF followed by polyubiquitination of RIP1. Peli1, a member of Pellino family of RING-like domain-containing E3 ubiquitin ligases, also participates in RIP1 polyubiquitination along with TRAF6 . The polyubiquitinated RIP1 recruits the ubiquitin receptor proteins TAB2 and TAB3, which in turn activate TAK1 . TAK1 then phosphorylates IKKα and IKKβ leading to degradation of IκB which results in the translocation of NF-κB to cell nucleus to stimulate proinflammatory cytokine production . Similar to MyD88 signaling, TAK1 activates AP1 through JNK and p38. TRIF also associates its adaptor protein NF-κB activating kinase- (NAK-) associated protein 1 (NAP1) to activate TBK1 and IKKε resulting in the phosphorylation and nuclear translocation of IRF3, inducing the expression of IFN-β . TRAF3 combines with the TBK1/IKKε complex and is also involved in the TRIF-mediated IRF3 activation . It is a unique signal pathway of TRIF that interacts with Fas-associated cell death domain (FADD) protein through RIP1 which in turn activates procaspase-8 to initiate cell apoptosis [262, 263]. Recently, a TIR-less splice variant of TRIF (designated as TRIS) was found capable of activating IRF3 through the interaction with TBK1 and/or activating NF-κB via RIP1 . TLR3 itself is also involved in signaling, for example, the phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain. Phosphorylated Tyr759 recruits PI3K to activate kinase Akt which in turn activates IRF3 in nucleus . Additionally, the phosphorylation of Tyr759 and Tyr858 induces degradation of IκB to release and partially activate NF-κB by phosphorylation . Tyrosine kinase c-Src also involves Akt activation .
4. Effects of TLR Activation on T Lymphocyte Subsets Differentiation
4.1. TLR Signals Affect Thymocytes Differentiation
Various viral infections through TLR interaction can induce type I IFN production. TLR3 recognizes ssRNA virus (West Nile virus), dsRNA virus (reovirus), respiratory syncytial virus, mouse cytomegalovirus (MCMV); TLR7 recognizes ssRNA viruses (vesicular stomatitis virus, influenza virus); TLR8 recognizes ssRNA from RNA virus; TLR9 recognizes dsDNA viruses (Herpes simplex virus, MCMV), CpG motifs from bacteria and viruses [268, 269]. Treatment of newborn mice with an active IFN-α2/α1 hybrid molecule reduced thymus cellularity by 85%. Phenotypic analysis revealed that the quantity of CD44+CD25− DN1 cells increased while that of CD44−CD25− DN4 cells decreased suggesting that the IFN-α2/α1 inhibition of T-cell development begins at an early progenitor stage . There are deleterious effects of IFN-α on T-cell development mediated by upregulation of cyclin-dependent kinase inhibitor p27Kip1 . The TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) and TLR7 ligand loxoribine are capable of inducing type I IFN expression resulting in a decrease in CD44−CD25+ DN3 population . Poly(I:C) can block the DN1-DN2 transition, diminish the DN3-DN4 cell proliferation, promote apoptosis of DP thymocytes, which culminate in a reduced thymic output . As poly(I:C) can activate the cytoplasmic helicases RIG-I and melanoma differentiation-associated gene 5 (MDA-5) pathways , the inhibitory effects of poly(I:C) on T-cell development may be not solely mediated by TLR3. Activation of MDA-5 causes a reduction in thymus size while TLR9 ligand CpG DNA and TLR4 ligand lipopolysaccharide (LPS) did not reduce thymus size . Upon stimulation by LPS, the gene expression of downstream signals of TLR3 and TLR4, that is, TRIF signal, is the most differentially affected pathway in murine thymocytes, suggesting a direct influence of altered TLR signaling on thymus involution .
4.2. Effects on T-Cell Differentiation through TLR Activation in APC
TLRs activation has been shown to bridge the innate and adaptive immunity [212, 276–278]. Beside its expression in professional APCs such as DCs and macrophages , TLRs can be expressed in T cells [254, 279, 280] and serve as co-stimulatory signals in T-cell activation [268, 277, 278, 281]. Traditionally, activation of TLRs in APCs would lead to the production of IFN-α, proinflammatory cytokines such as TNF-α, IL-1 and IL-6, and the cytokines IL-12 and IL-18 that instruct Th1 to differentiate, whereas an increased Th2 response was observed in MyD88 deficient mice with impaired TLRs signaling [282–284]. The IL-12 and IL-23 secretions of DCs induced by TLRs activation are enhanced by chemokine CCL17 in an autocrine manner. The productions of these cytokines are significantly reduced in CCL17-deficient DCs . It has been demonstrated that the dose of antigen plays an important role in directing Th1/Th2 differentiation driving by DCs. A lower concentration of ovalbumin (OVA) peptide (1 and 10 ng/mL) induced Th2 commitment while higher concentrations (1 μg/mL and 100 ng/mL) failed to elicit Th2 development. Stimulation of CD4+ T cells with DCs along with TLR2 or TLR9 agonists in the presence of the 10 ng/mL of OVA peptide, the optimal antigen concentration for Th2 development resulted in suppression of IL-4 production and Th2 development. This suggests that TLR-activated DCs can block Th2 lineage commitment independent of antigen dosage . A lower dose of LPS (0.1 μg), through TLR4 signaling, induced a Th2 response to inhaled antigens in a murine allergic sensitization model. In contrast, high doses of LPS (100 μg) with antigen resulted in a Th1 response . However, repeated administration of TLR2 ligand Pam3CSK4 or TLR4 ligand LPS leads to tolerance of TLR2  or TLR4  with reduced cytokine release and expression of IRAK-1 and IRAK-4 proteins . Additionally, activation of TLR4 resulted in a MyD88-dependent Th17 response in memory CD4+ T cells in the absence of TRIF molecule . Activation of DCs via TLR2-MyD88 also induced Th1 and Th17 cell differentiation . Still, signaling of TLR2 can inhibit DCs to produce IL-12p70 by dampening the type 1 IFN amplification loop. This signaling also drives the immune response induced by synergistic combination of TLR4 and TLR7/8 agonists (both are potent inducers of Th1 responses) toward Th2 and Th17 responses in the naive and memory T-cell subpopulations . Murine DCs activated by LPS or CpG oligodeoxynucleotide (ODN) overcame Treg-mediated suppression by inducing IL-6 signals . IL-6 also mediates the downregulation of Foxp3 expression in T cells induced by TLR7-activated DCs . However, activation of TLR7 by resiquimod in OVA-induced experimental model of murine allergic asthma resulted in expansion of Treg cell through a TGF-β-dependent pathway . Thus, it seems that T-cell subsets activated by TLR signals from APCs vary depending on the type and the status of APC involved, the cytokine milieu, as well as the amount of the antigen present [295–297].
On the other hand, a recent report indicated that signals from Th cells can govern the formation and function of specialized DC subsets, for example, Th1 and Th17 cells cause monocytes differentiation into Th1- or Th17-promoting DC subsets in psoriasis lesion, and Th2 cells induce the production of Th2-promoting DC subset in acute atopic dermatitis . The phenotype of these polarized DC subsets cannot be altered even after subsequent stimulation of TLR ligands. With stimulation by ligands of TLR1-TLR9, the quantities of cytokine secreted by the specialized DC subset were changed but the overall cytokine secretion profile remained the same . The TLR signaling in DCs is negatively regulated by adapters containing immunoreceptor tyrosine-based activation motif (ITAM) sequences to suppress activation of DCs , for example, DNAX-activating protein of molecular mass 12 kilodaltons (DAP12) in mDCs  and Fc receptors for IgG in pDCs . The triggering receptor expressed on myeloid cell-2 (TREM-2) associates DAP12 to suppress TLR signaling in bone-marrow-derived DCs . The ligand of TREM-2 is also detected on the surface of these DCs. Thus, it seems that the preexisting polarized immunity dictates that the subsequent immune response and this polarization will not be altered even if stimulated by PRR.
4.3. Direct Activation of TLR in CD4+ T Effector Cells Induces Costimulation
The expression and the activity of TLRs in T cells are related to the functional status, for example, effector or memory cells and central memory or effector memory cells as well as the activation status of T cells by TCR signals (Table 1) [268, 277, 303]. Murine naive T cells can express TLR1-TLR9 although there is a considerable variation in expression levels . TLR1, TLR4 and TLR6 were among those maximally expressed in CD4+ and CD8+ T cells . Although naive human CD4+ T cells express significant levels of intracellular TLR2 and TLR4 protein, cell surface expression of TLR2 and TLR4 was found only in activated CD4+ T cells . Cell surface expression of TLR2 in CD4+CD45RO+ (memory) T cells is significantly higher than that of CD4+CD45RA+ (naive) T cells. However, TLR2 expression by naive T cells can be significantly increased by anti-CD3 activating TCR. This is enhanced by TLR2 ligand. An activation marker, HLA-DR antigen, was found coexpressed with TLR2 in parallel suggesting that TLR2 expression is associated with T-cell activation . Similar results were also obtained in CD8+ T cells with transcript copies of TLR2 mRNA in CTLs 7–10 times higher than that in naive CD8+ T cells . However, TLR expression in T cells is controversial. When poly(I:C) and CpG DNA were added to murine CD4+ T-cell cultures that were TCR activated by anti-CD3 antibody, TLR3 and TLR9 expression was upregulated with enhanced survival. By contrast, levels of TLR2, TLR4 were undetectable when peptidoglycan and LPS were used . Activated murine CD4+CD25− effector T cells can functionally express TLR2 . The discrepancy may be attributed in part to the different protocols used for T-cell purification and the different ligands used for TLR activation. A study compared the differences in purity, activation requirements, specifically, the response to TLR ligands of human CD4+ T cells isolated by immunomagnetic cell sorting (IMACS-CD4+) or by IMACS followed by fluorescence-activated cell sorting (FACS, IMACS/FACS-CD4+) . It showed that the IMACS/FACS-CD4+ T cells were highly purified (99.7%) and when stimulated by TLR4 ligand LPS, in the absence of TCR activation by anti-CD3 and costimulation from anti-CD28, did not elicit a response. On the other hand, a less pure sample of IMACS-CD4+ T cells (92.5%) showed IL-2 and IFN-γ secretion responding to anti-CD3 without anti-CD28. Stimulation with anti-CD3, anti-CD28 and LPS significantly increased proliferation and cytokine production of IMACS-CD4+ but not IMACS/FACS-CD4+ T cells. The expression of TLR4 was also significantly higher in IMACS-CD4+ cells than in IMACS/FACS-CD4+ cells. This difference is likely to be the result of contaminating accessory cells in IMACS-CD4+ population . Another report using LPS derived from Salmonella enteritidis, Salmonella minnesota and Salmonella typhimurium demonstrated that only LPS from Salmonella typhimurium can induce proliferation and IFN-γ secretion in murine CD4+ T cells .
TLRs expressed in T cells have been suggested to act as co-stimulatory molecules involved in T-cell activation [268, 277]. Application of Pam3CysSK4, the ligand of TLR1/TLR2 complex, in activated TCR transgenic mice CD8+ T cells resulted in increased cell proliferation and survival. This was associated with a sustained CD25 expression and an enhanced expression of Bcl-xL, an antiapoptotic molecule. TLR2 engagement also enhances production of IFN-γ and granzyme B, promotes cytotoxic activity of antigen-activated CD8+ T cells, reduces the activation requirements for co-stimulatory signals from APC and TCR signal strength, and generates efficient memory T cells in response to a weak TCR signal [308, 309]. TLR2 engagement on CD8+ memory T cells is also involved in the direct control of memory cell proliferation and IFN-γ production . The co-stimulatory role of TLR2 ligation on CD8+ T cell is believed to be due to the intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8+ T cells [308, 311]. PI3K signal activated by MyD88 adaptor is indispensable to the costimulation of CD4+ T cells by TLR9 ligand CpG ODN . Costimulation by poly(I:C) of naive CD4+ T cells through TLR3 in the presence of anti-CD3 and anti-CD28 can induce synthesis of IL-17A and IL-21, this being dependent on activation of the NF-κB pathway. IL-17A and IL-21 cause naive CD4+ T-cell differentiation toward an IL-21 phenotype. These cells do not have the transcription factors T-bet, GATA-3 and ROR-c that represent the induction of Th1, Th2 and Th17 subsets, respectively  and consequently such cells are absent. TLR ligands can act directly on highly purified T cells in the absence of CD28 engagement  but is unable to induce functional responses in naive T cells without concurrent TCR stimulation . Therefore, TLR-induced signals in T cells are strictly co-stimulatory  (Figure 7).
4.4. Effects of Direct Activation of TLR on Treg Cells
TLR2 agonist Pam3Cys acts directly on purified Treg cells resulting in an augmented Treg cells proliferation. This is accompanied by a temporal loss of the suppressive Treg phenotype in the presence of TCR stimulation  and a transient suppression of Foxp3 expression . The effects of a reversal of suppression on responder T cells by human CD4+CD25+Foxp3+ Treg cells influenced by the TLR2 ligand were Akt being phosphorylated and p27Kip1 (The cyclin-dependent kinase inhibitor which is highly expressed in Tregs and capable of arresting cell-cycle in the G1 phase, and can be reduced by IL-2) being downregulated. There was no alteration in Foxp3 expression . On the other hand, engagement of TLR2 resulted in human CD8+CD25+Foxp3+ Treg cells expansion that directly suppressed CD4+ T-cells proliferation by cell-contact inhibition and triggered CD4+CD45RO+ memory T-cell apoptosis inhibiting allergen induced Th2 immune responses . Treg cells are able to regain their suppressive property in the presence of IL-2 once the TLR2 ligand is removed [306, 314]. Although TLR2-stimulated Treg cells readily lost their ability to suppress proliferation of effector T cells, cytokine production by effector T cells was still repressed. This suggests that the activity of Treg cells was cytokines independent . Treg and Th17 cells are considered divergent and mutually inhibitory. It has been reported that when naive CD4+ T cells were stimulated with TLR2 agonists Th17 differentiation in vitro and Th17 cytokine production occurred . Thus, the reduced suppressive function of Treg cells induced by TLR2 stimulation may be a result of imbalanced phenotype and function between Treg and Th17 . The suppression seen in both CD4+CD25hiFoxp3lowCD45RA+ naive and CD4+CD25hiFoxp3hiCD45RA− memory or effector Treg cells on CD4+CD25-Foxp3-CD45RA+ naive responder T cells can be reversed by activated TLR1/2. This is accompanied by increased production of IL-6 and IL-17, upregulation of ROR-c and downregulation of Foxp3 expression . Pam3Cys-mediated reduction of Treg suppressive function can be abrogated by neutralization of IL-6 or IL-17 . All together, in a bacterial infection, the TLR2 ligand augments the functional activities and the clonal expansion of effector T cells as well as temporarily attenuating the suppressive function of Treg cells against the invading pathogen. The TLR2 signal also promotes the expansion of Treg cells that have reduced suppressive function. As the TLR9 ligand can reprogram Treg population toward Th17 differentiation [320, 321], it is conceivable that TLR2 may play a role in Treg cell reprogramming. The proinflammatory cytokines IL-6 and IL-1β are crucial reprogramming cytokines of Treg cells toward Th17 differentiation [322, 323]. When a pathogen is eliminated, the expanded clusters of Treg cells recover their suppressive activity preventing autoimmunity that may result from over activated effectors (Figure 1) [303, 306, 324]. However, it is not known whether the changes observed in reprogrammed Treg cells can be reversed.
Pam3CSK4, a TLR1/TLR2 ligand can induce tumor remission in severe combined immunodeficiency (SCID) mice by diminishing the suppressive function of Foxp3+ Treg cells and enhancing the cytotoxicity of tumor-specific CTLs. Adoptive transfer of CTLs and Treg cells pretreated with Pam3CSK4 from wild-type mice into tumor-bearing SCID mice can restore antitumor immunity in SCID mice by reciprocal downregulation of Treg cells and upregulation of CTL function . However, treatment of CD4+CD25+ Treg cells with intrinsic TLR2 agonist, heat shock protein (HSP) 60, before anti-CD3 activation significantly enhanced the suppressive ability of the Treg cells to inhibit CD4+CD25− or CD8+ T-cell proliferation, IFN-γ and TNF-α secretion . Nevertheless, the purity of CD4+CD25+ Treg cells used being >90% implies possible contamination of other cell types. Not all the CD4+CD25+Foxp3+ cells from peripheral blood activated by HSP60 are Treg cells. Activated CD4+ effector T cells can also transiently express Foxp3. It should be noted that only cells with CD4+CD25+Foxp3+CD30+ phenotype possess suppressive function. This induction of Treg cells by HSP60 is enhanced by signaling via TLR4 on APCs . Thus, contaminated APCs within the Treg cell population may promote the suppressive function of Treg cells by TLR4 signaling triggered by HSP60 in APC rather than by TLR2 signaling in Treg possibly accounting for this discrepancy. Indeed, TLR2 expression in human CD4+CD25+CD127− Treg cells isolated from peripheral blood mononuclear cells is not present .
Activation of TLR4 in CD4+CD25+ Treg cells by LPS, in the absence of APC, can directly induce Treg cells activation. This activation involves the upregulation of activation markers, for example, CD69, CD44, CD38, as well as B7-1 and promotes cellular survival and proliferation . TLR4 expression can be detected in peripheral human CD4+CD25+ Treg cells. Co-culture of these Treg cells with LPS induced activation of Treg cells with decreased expression of Foxp3. These cells repressed neutrophils in an IL-10- and TGF-β-dependent manner . However, the enhancement of Treg cell function by LPS was not reproduced by other investigators [306, 314, 331]. It is possible that potential contamination of commercial LPS preparations with TLR2 ligands  or the presence of impurities of the cells  may create discrepant results [306, 314, 331]. Application of TLR5 agonist flagellin augments the suppressive capacity of CD4+CD25+ Treg cells with enhanced expression of Foxp3. CD4+CD25+ Treg cells can suppress effector T cells in a ratio of 1 : 81 and this inhibition was increased to 1 : 243 with the addition of flagellin . TLR8 is exclusively expressed in human Treg cells, and triggering of TLR8-MyD88-IRAK4 signaling pathway can reverse the suppressive function of Treg cells . A co-stimulatory effect of CpG DNA on CD4+CD25− effector T cells is to abrogate the suppression by Treg cells . CpG DNA can also directly act on CD4+CD25+ Treg cells to inhibit its suppressive effects . Thus, the direct effect of individual TLR ligand on Treg cell is completely different although almost all of the TLR signals share a common pathway (Table 1).
Treg cells’ phenotypic plasticity is seen by their expression of proinflammatory cytokines such as IL-17, IFN-γ, or IL-2 under certain conditions and their reprogramming into Th-like cells [321, 322]. Mice systemically administering high doses of CpG ODN at 50–100 μg/mouse show activation of naive Treg cells in the spleen to acquire potent suppressor activity. This was mediated by the immunoregulatory enzyme IDO in pDCs. When IDO was blocked, CpG treatment stimulated pDCs to express IL-6 which in turn reprogrammed Foxp3 lineage Tregs to express IL-17 to become Th17-like effector T cells [335, 336]. The converted Treg cells play a helper role essential for initial priming of CD8+ T cells to a new cross-presented antigen. This was CD40L dependent. This process, unlike the help from conventional non-Treg CD4+ cells, did not require preactivation or prior exposure to antigen . CD4+Foxp3+ Treg cells can also be reprogrammed into Tfh lineage in mouse Peyer’s patches under the interaction with B cells and loss of Foxp3 expression . Although the reprogramming of Treg cell has been recognized to play a critical role in the initiation of certain innate immune responses by vaccination with a TLR agonist adjuvant, that is, CpG ODN [320, 321, 338, 339], the effects of the activation of other TLRs besides TLR9 on reprogramming of T cells especially Treg cells are not known.
4.5. Modulation of CD8+ T-Cell Response by TLR Activation
Viral antigen taken up by APCs are processed into epitopes, loaded onto MHC-I molecules and cross-presented to CD8+ T cells eliciting an anti-virus CD8+ T-cell response. However, not all the potential epitopes can be equally cross-presented to CD8+ T cells. The epitopes recognized by the most abundant cognate T-cell populations are referred to as being immunodominant, while those recognized by less abundant T-cell populations are named as subdominant determinants. Thus, the immunodominant and subdominant determinants constitute a hierarchy (α-, β-, etc.) in an antiviral immune response . This can be altered by TLR signals. Combined activation of TLR2 and TLR3 by Pam3cysk4 and poly(I:C) at the infection site of lymphocytic choriomeningitis virus (LCMV) in mice reduced antigen uptake and cross-presentation of an immunodominant determinant of LCMV, NP396 and shifted it becoming a subdominant determinant. However, administration of TLR4 ligand LPS did not induce this shift . Therefore, combined activation of multiple TLRs could possibly induce a complex response instead of being merely synergistic or antagonistic.
4.6. Effects of TLR Activation on Peripheral T-Cell Tolerance
The outcome of presentation by DCs depends on its activation status. DCs activated by PAMPs, for example, TLR ligands from invading pathogen will be capable of producing co-stimulatory molecules and proinflammatory cytokines immunogenic. On the other hand, self-antigen from apoptotic self-cells lack TLR ligands and cannot induce maturation of DCs and this eventually results in tolerance [342, 343]. However, a tumor-associate antigen NY-ESO-1 was able to induce T-cell dependent antibody response through activation of TLR4 on DCs . In addition, mature DCs induced by distinct stimulation may function differently. A recent study suggested that LPS matured DCs produced IL-12 to promote CD8+ T-cell trafficking and inflammation, whereas poly(I:C) matured DCs facilitate CD8+ T-cell infiltration and autoimmunity in an IFN-α-dependent manner . Mesenchymal stem cells can inhibit DCs activation induced by LPS, block DCs migration to draining lymph node and impair its capacities to prime CD4+ T cells and cross-presentation to CD8+ T cells . The cross-talk between different DC subsets is also important. The cDCs are indispensable for cross-presentation of cancer antigens in eliciting potent anticancer immunity. The efficacy of CpG in anticancer immunotherapy is dependent on activation of TLR9 in pDCs. CpG-activated pDCs induce upregulation of co-stimulatory molecule CD80 in cDCs, thus providing an adjuvant effect in anticancer immunotherapy . Some specific DC subsets may be primarily tolerogenic even if activated. For example, a prototypic DC subset, Langerhans cells is found precommitted tolerogenic and unable to translocate RelB, an NF-κB family member, to the nucleus . However, although Langerhans cells are tolerogenic to bacteria without cell surface expression of TLRs, they can effectively sense virus and poly(I:C) to induce naive CD8+ T-cells expansion and differentiation into effector cells that are dependent on high expression of CD70 rather than mediated by IL-12 . Therefore, mature DCs are not a homogenous population and instead a cell family with increasing new subset member being discovered . They may function divergently depending on its activation status  and other factors such as the quality of stimulation, the communication between different DC subsets and the nature of DC subset.
Human monocytes, when cultured with Wnt5a and subsequently stimulated by TLR ligands, can differentiate into DCs. Enhanced production of inhibitory ligands PD-L1 and PD-L2 rather than upregulation of CD83, HLA-DR, CD40, CD86, CD80 and CCR7 molecules would also occur . Additionally, these cells secrete low levels of IL-12p70 and TNF-α, however, there is an increased production of regulatory cytokine IL-10 with a reduced capacity of Th1 response. This tolerogenic DC induction by enhanced Wnt signaling is β-catenin independent but is dependent on noncanonical Ca2+/calmodulin-dependent protein kinase II/NF-κB signaling . Lymph node cells that have precommitted tolerant of self-antigen proteolipid protein, when stimulated by both CpG ODN and this protein, divided and differentiated into Th1 cell lineage. This is IL-12 dependent and these cells are capable of inducing autoimmune encephalomyelitis when they are transferred into naive mice . The break of this cross-tolerance depends on the specific CD4+ T-cell help and stimulation by sole TLR ligands without the help from CD4+ T cell is insufficient to overcome this tolerance . By contrast, induction of TLR signaling in T cells may increase tolerance. T-cell intrinsic TRAF6 is essential in the maintenance of peripheral tolerance. Deletion of TRAF6 in T cells leads to hyperactivation of PI3K-Akt pathway and increased resistance of T effector cells to the suppression by CD4+CD25+ Treg cells. This finally results in multiorgan inflammatory disease . As TRAF6 is an important adaptor in TLR signaling, it is conceivable that activation of TLRs expressed in T cells may involve in maintenance of T-cell susceptibility to Treg cells via TRAF6.
Administration of TLR3 ligand poly(I:C) results in a strong expression of PD-1 ligand (PD-L1) in all subsets of LNSCs . This may prevent the tolerized T cells in lymph nodes regaining their effector function. However, this also implies that a virus infection in LNSCs such as FRCs would not be eliminated hence becoming a persistent infection . Activation of TLR3 by poly(I:C) also induces upregulation of MHC-I and co-stimulatory molecules in LNSCs, for example, CD80 and CD86 in FRCs, CD80 in LECs . The net result of promoting immune response by enhanced expression of MHC-I and co-stimulatory molecules and promoting tolerance by augmented expression of PD-L1 is a decreased ability of FRCs to stimulate T-cell division in the presence of poly(I:C). However, the phenotypic alterations of these FRCs in PD-L1, MHC-I and co-stimulatory molecules such as CD80 and CD86 are similar to the DCs being treated by poly(I:C) . The decreased stimulatory ability of these FRCs is considered to be the consequence of deduced production of specific antigen by FRCs . Alternatively, this varying stimulatory capacity between FRCs and DCs may be due to the altered TLR signaling cascades in FRCs being tolerogenic cells .
The discrimination of self or nonself antigen by DCs is also TLR dependent . TLRs control the TCR ligand generation in phagosome autonomously. With the conjugation of TLR ligand, the phagocytosed antigen by DCs can be selectively loaded on MHC-II molecules and preferentially presented in the context of costimulation . Activation of TLRs is helpful to break tolerance in immunocompromised individuals. Blockade of CTLA4 or PD-1 in combination of TLR9 agonist CpG ODN treatment overcomes immune tolerance in tumor bearing mice with improved long-term survival, increased tumor-specific effector T-cell population and decreased Treg cell levels .
4.7. Effects of TLR Activation on Mucosal Tolerance
TLRs are directly involved in mucosal tolerance development. PAMPs from nonpathogenic commensal microorganisms in mucosa are also termed microbe-associated molecular patterns (MAMPs) .
TLR1, TLR2, TLR3, TLR4 and TLR5 as well as TLR9 proteins have been found expressed both in human small intestines and colon . However, their expression and action in enterocytes are different even within the same cell. Activation of TLR9 through apical and basolateral surface domains of intestinal epithelial cell (iEC) results in distinct transcriptional responses. Basolateral activation of TLR9 induces IκBα degradation and activation of the canonical NF-κB signal pathway. Apical TLR9 stimulation elicits a unique response with accumulation of ubiquitinated IκBα in cytoplasm-suppressing NF-κB activation. This results in intracellular tolerance to subsequent TLR9 basolateral challenge. It also blocks apical TLR2 and basolateral TLR3 or TLR5 stimulation . However, apical engagement of TLR3 or TLR5 is unable to induce tolerance to subsequent basolateral TLR stimulation . Nasal vaccination of OVA adjuvanted by CpG overcame the nasal tolerance and induced strong Th1 and Th2 responses through activation of TLR9 . This contrasts with the responses of commensal bacteria that suppress Th17 response via TLR pathway to create an immune tolerance niche for colonization. TLR2 on CD4+ T cells can be activated by polysaccharide A from Bacteroides fragilis but not other TLR2 ligands to induce IL-10 production in the absence of APCs. Specifically, polysaccharide A treated CD4+Foxp3+ Treg cells display a more potent TLR2-dependent suppressive capacity than those treated by other TLR2 ligands .
The mechanism of TLR in maintaining intestinal homeostasis is not fully understood. TLR hyporesponsiveness to commensal microbiota has been suggested to play an important role in keeping homeostasis in the gut. Several mechanisms to account for this hyporesponsiveness include downregulating TLR surface expression and upregulated inhibitory Toll interacting protein with reduced phosphorylation of IRAK . The hyporesponsiveness of intestinal DCs to TLR ligand engagement appears limited to TLR4 . Activation of TLR3 by poly(I:C) in iECs induced retinoic acid early inducible-1 production breaks self-tolerance . Thus, without commensal microbiota, the engagement of TLR in gut epithelial cells from fetal or germ-free animals can induce an inflammatory response. iECs develop TLR tolerance immediately after commensal microbial colonization [366, 367]. It has been suggested that microRNA-146a-mediated translational repression and degradation of IRAK1 are responsible for the induction of neonatal innate immune tolerance in intestinal epithelium . The activation of TLR3, TLR4, TLR5 and TLR9 in iECs induces mitogen-activated protein kinase phosphatase-1 (MKP-1) mediated by NF-κB signaling. MKP-1 plays an important role in the development of tolerance to TLR engagement . Immunity to bacterial infection is tampered in TLR adaptor MyD88 deficient mice [370–372]. The absence of TLRs or MyD88 increased susceptibility to DSS-induced experimental colitis . Administration of TLR ligands in these animals prevents the development of colitis . Therefore, a base level of TLR signaling from the luminal commensal microbiota is required to maintain intestinal homeostasis .
A variety of DCs have been identified in intestine . pDCs play an important role in the development of oral tolerance. Orally ingested antigen is presented to T cells in liver by pDCs to induce T-cell anergy or lineage deletion through a CD4+ T-cell-independent mechanism [375, 376]. The output of DCs from lamina propria can be increased 20–30 fold by oral administration of TLR7/8 ligand resiquimod . The activation of TLR in iECs also augmented the DCs sampling of antigen through their extension into gut lumen . Stimulation of human monocyte-derived macrophages with a Gram-positive commensal Lactobacillus rhamnosus GG or a Gram-positive pathogenic Streptococcus pyogenes demonstrated that both the bacteria can promote TLR2 expression in macrophages. However, only pathogenic bacteria are capable of augmenting IFN-α/β-dependent TLR3 and TLR7 gene expression. Thus, it suggested that human macrophages can discriminate the presence between commensal and pathogenic bacteria by IFN-mediated TLR gene regulation [378, 379]. Intestinal DCs also play a similar discriminative role in identification of commensal or pathogenic agents and the subsequent decision between tolerance and immunity in intestines .
5. Conclusive and Perspective Remarks
T cells play a central role in the cell-mediated immunity of the host. All subsets of T cells originate from thymocytes in thymus where they acquire their surface TCR repertoires and develop the primary phenotypic markers then migrate to peripheral lymphatic organ. Upon detection of infectious agents, T cells are activated and differentiate into effector T cells or Treg cells. TLRs are canonical members of PRRs capable of inducing T-cell activation through cross-presentation of APCs or directly acting on T cells. Activation of all the identified TLRs except TLR3 results in signaling through the MyD88-NF-κB pathway. It is not known why activation of TLRs by different ligands results in different outcomes although they act via a common pathway.
The lymph node is the major peripheral lymph organ where antigen-specific responses or tolerance is triggered. As inflammation is a prerequisite to induce immune responses rather than tolerance, it is conceivable that delivery of inflammatory cytokines such as IL-12, IFN-γ to the tumor or its draining lymph node would be helpful to overcome the immunocompromised status in some patients, for example, in cancer patients. Thus, the immunity against cancer which has been suppressed would be reestablished in the cancer-bearing host. Indeed, intrinsic IL-12 is capable of converting Foxp3+ Treg cells into IFN-γ+ Th1, IL-17+ Th17, or Foxp3+IFN-γ+/Foxp3+IL-17+/Foxp3+IFN-γ+IL-17+ transitional cells. The transitional Foxp3+IFN-γ+ cells further differentiate into IFN-γ+ Th1 cells but not Foxp3+ Treg cells although they still retain their regulatory functions at this stage . Intratumoral delivery of IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF) recruits immunogenic DCs to tumors and later migrates to the local draining lymph nodes. However, these cells have a short half life and become IDO-positive tolerogenic DCs after a few days. Interestingly, the initial recruitment and activation of DCs as well as the subsequent switch to tolerogenic activity are both under the influence of IFN-γ . It would be of interest to note whether the delivery of IL-12 to the lymph node would maintain or restore these DCs immunogenic.
Current studies support the concept of reprogramming of TLR ligands, for example, CpG ODN on Treg cells. This raises the question of whether it might be possible to overcome the immunosuppressive effects of Treg cells, for example, in patients with disordered immunity. Indeed should the Th cell be reprogrammable, the roadmap of autoimmunity therapy and/or other types of therapy would have to be reevaluated. Some disorders of immunity requiring enhanced immunosuppression can occur in the context of liver transplantation , kidney transplantation , or stem cell transplantation  to name a few examples. Exploiting such pathways could lead to the development of new therapeutic agents against immune disorders.
|AP1:||Activator protein 1|
|Bcl-6:||B cell lymphoma 6|
|Bim:||Bcl-2-interacting mediator of cell death|
|Blimp-1:||B lymphocyte-induced maturation protein 1|
|CCR:||C-C chemokine receptor|
|CLR:||C-type lectin receptor|
|CpG:||Unmethylated cytosine preceding guanosine motif|
|cTEC:||Cortical thymic epithelial cell|
|CTL:||Cytotoxic T lymphocyte|
|CTLA-4:||Cytotoxic T lymphocyte-associated antigen-4|
|CXCR:||C-X-C chemokine receptor|
|DAP12:||DNAX-activating protein of molecular mass 12 kilodaltons|
|Deaf1:||Deformed epidermal autoregulatory factor 1|
|DSS:||Dextran sulfate sodium|
|FACS:||Fluorescence-activated cell sorting|
|FADD:||Fas-associated cell death domain|
|Foxp3:||Forkhead box P3|
|GALT:||Gut-associated lymphoid tissue|
|GATA transcription factors:||A family of transcription factors capable of binding to the DNA sequence “GATA”|
|GM-CSF:||Granulocyte macrophage colony-stimulating factor|
|HSP:||Heat shock protein|
|IDO:||Indoleamine 2, 3-dioxygenase|
|iEC:||Intestinal epithelial cells|
|IKK:||Inhibitor of κB kinase|
|IMACS:||Immunomagnetic cell sorting|
|IRF:||Interferon regulatory factor|
|iTreg:||Inducible regulatory T cell|
|IκB:||Inhibitor of κB|
|ITAM:||Immunoreceptor tyrosine-based activation motif|
|JNK:||c-Jun N-terminal kinase|
|LCMV:||Lymphocytic choriomeningitis virus|
|LEC:||Lymphatic endothelial cell|
|LNSC:||Lymph node stromal cell|
|MAMP:||Microbe-associated molecular patterns|
|MDA-5:||Melanoma differentiation-associated gene 5|
|MKP-1:||Mitogen-activated protein kinase phosphatase-1|
|mTEC:||Medullary thymic epithelial cell|
|MyD88:||Myeloid differentiation factor 88|
|NAK:||NF-κB activating kinase|
|NAP:||NF-κB activating kinase-associated protein|
|NEMO:||NF-κB essential modulator|
|NF-κB:||Nuclear factor κB|
|NLR:||Nucleotide binding domain and leucine-rich repeat containing gene family|
|nTreg:||Natural regulatory T cell|
|PAMP:||Pathogen-associated molecular patterns|
|PD-1:||Programmed death 1|
|PRR:||Pattern recognition receptor|
|PTA:||Peripheral tissue-restricted antigen|
|RHIM:||Receptor-interacting protein homotypic interaction motif|
|RIG-I:||Retinoic acid-inducible gene-I|
|RLR:||Retinoic acid-inducible gene-I-like receptor|
|ROR:||Retinoic acid receptor related orphan receptor|
|RTE:||Recent thymic emigrants|
|SCID:||Severe combined immunodeficiency|
|Sos1:||Son of sevenless gene 1|
|STAT:||Signal transducer and activator of transcription|
|TAB:||Transforming growth factor β-activated kinase-1 binding protein|
|TAK:||Transforming growth factor β-activated kinase|
|T-bet:||T box expressed in T cell|
|TBK:||TRAF family member-associated NF-κB activator-binding kinase|
|TCF-1:||T-cell factor 1|
|Tcm:||Central memory T cell|
|Tem:||Effector memory T cells|
|Tfh:||T follicular helper cell|
|TGF:||Transforming growth factor|
|Th:||T helper cell|
|TICAM-1:||TIR domain containing adaptor molecule-1|
|TIR:||Toll/IL-1 receptor domain|
|TIRAP:||TIR domain-containing adapter protein|
|TNF:||Tumor necrosis factor|
|TRAF:||Tumor necrosis factor receptor associated factor|
|TRAM:||TRIF-related adaptor molecule|
|TREM-2:||Triggering receptor expressed on myeloid cell-2|
|TRIF:||TIR domain-containing adaptor inducing interferon-β|
|Tscm:||Memory stem T cells.|
Conflict of Interests
The authors declare no conflict of interests.
- C. A. Janeway Jr., “Approaching the asymptote? Evolution and revolution in immunology,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 54, no. 1, pp. 1–13, 1989.
- C. A. Janeway Jr., “The immune system evolved to discriminate infectious nonself from noninfectious self,” Immunology Today, vol. 13, no. 1, pp. 11–16, 1992.
- R. Medzhitov and C. A. Janeway Jr., “Decoding the patterns of self and nonself by the innate immune system,” Science, vol. 296, no. 5566, pp. 298–300, 2002.
- H. Kumar, T. Kawai, and S. Akira, “Pathogen recognition by the innate immune system,” International Reviews of Immunology, vol. 30, no. 1, pp. 16–34, 2011.
- G. Hajishengallis and J. D. Lambris, “Microbial manipulation of receptor crosstalk in innate immunity,” Nature Reviews Immunology, vol. 11, no. 3, pp. 187–200, 2011.
- F. Osorio and C. Reis e Sousa, “Myeloid C-type lectin receptors in pathogen recognition and host defense,” Immunity, vol. 34, no. 5, pp. 651–664, 2011.
- H. Kumar, T. Kawai, and S. Akira, “Toll-like receptors and innate immunity,” Biochemical and Biophysical Research Communications, vol. 388, no. 4, pp. 621–625, 2009.
- P. Ranjan, J. B. Bowzard, J. W. Schwerzmann, V. Jeisy-Scott, T. Fujita, and S. Sambhara, “Cytoplasmic nucleic acid sensors in antiviral immunity,” Trends in Molecular Medicine, vol. 15, no. 8, pp. 359–368, 2009.
- H. Yanai, D. Savitsky, T. Tamura, and T. Taniguchi, “Regulation of the cytosolic DNA-sensing system in innate immunity: a current view,” Current Opinion in Immunology, vol. 21, no. 1, pp. 17–22, 2009.
- Z. Wang, M. K. Choi, T. Ban et al., “Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 14, pp. 5477–5482, 2008.
- S. Sharma and K. A. Fitzgerald, “Innate immune sensing of DNA,” PLoS Pathogens, vol. 7, no. 4, Article ID e1001310, 2011.
- R. Medzhitov, P. Preston-Hurlburt, and C. A. Janeway, “A human homologue of the Drosophila toll protein signals activation of adaptive immunity,” Nature, vol. 388, no. 6640, pp. 394–397, 1997.
- L. C. Parker, L. R. Prince, and I. Sabroe, “Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity,” Clinical and Experimental Immunology, vol. 147, no. 2, pp. 199–207, 2007.
- C. Pasare and R. Medzhitov, “Control of B-cell responses by Toll-like receptors,” Nature, vol. 438, no. 7066, pp. 364–368, 2005.
- N. W. Palm and R. Medzhitov, “Pattern recognition receptors and control of adaptive immunity,” Immunological Reviews, vol. 227, no. 1, pp. 221–233, 2009.
- A. Tuettenberg, C. Becker, A. Correll, K. Steinbrink, and H. Jonuleit, “Immune regulation by dendritic cells and T cells—basic science, diagnostic, and clinical application,” Clinical Laboratory, vol. 57, no. 1-2, pp. 1–12, 2011.
- V. Appay, R. A. W. Van Lier, F. Sallusto, and M. Roederer, “Phenotype and function of human T lymphocyte subsets: consensus and issues,” Cytometry Part A, vol. 73, no. 11, pp. 975–983, 2008.
- B. J. Fowlkes, L. Edison, B. J. Mathieson, and T. M. Chused, “Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells,” Journal of Experimental Medicine, vol. 162, no. 3, pp. 802–822, 1985.
- N. M. Le Douarin and F. V. Jotereau, “Tracing of cells of the avian thymus through embryonic life in interspecific chimeras,” Journal of Experimental Medicine, vol. 142, no. 1, pp. 17–40, 1975.
- P. E. Love and A. Bhandoola, “Signal integration and crosstalk during thymocyte migration and emigration,” Nature Reviews Immunology, vol. 11, no. 7, pp. 469–477, 2011.
- J. Li, N. Iwanami, Q. H. Vu, M. Furutani-Seiki, and Y. Takahama, “Noninvasive intravital imaging of thymocyte dynamics in Medaka,” Journal of Immunology, vol. 179, no. 3, pp. 1605–1615, 2007.
- F. M. V. Rossi, S. Y. Corbel, J. S. Merzaban et al., “Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1,” Nature Immunology, vol. 6, no. 6, pp. 626–634, 2005.
- C. Liu, F. Saito, Z. Liu et al., “Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization,” Blood, vol. 108, no. 8, pp. 2531–2539, 2006.
- R. Scollay, P. Bartlett, and K. Shortman, “T cell development in the adult murine thymus: changes in the expression of the surface antigens Ly2, L3T4 and B2A2 during development from early precursor cells to emigrants,” Immunological Reviews, vol. 82, pp. 79–103, 1984.
- S. Habu, M. Kimura, M. Katsuki, K. Hioki, and T. Nomura, “Correlation of T cell receptor gene rearrangements to T cell surface antigen expression and to serum immunoglobulin level in scid mice,” European Journal of Immunology, vol. 17, no. 10, pp. 1467–1471, 1987.
- E. F. Lind, S. E. Prockop, H. E. Porritt, and H. T. Petrie, “Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development,” Journal of Experimental Medicine, vol. 194, no. 2, pp. 127–134, 2001.
- J. C. Zúñiga-Pflücker, “The original intrathymic progenitor from which T cells originate,” Journal of Immunology, vol. 183, no. 1, pp. 3–4, 2009.
- Y. Takahama, E. W. Shores, and A. Singer, “Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells,” Science, vol. 258, no. 5082, pp. 653–656, 1992.
- R. L. Kortum, C. L. Sommers, C. P. Alexander et al., “Targeted Sos1 deletion reveals its critical role in early T-cell development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 30, pp. 12407–12412, 2011.
- T. Nitta, S. Murata, T. Ueno, K. Tanaka, and Y. Takahama, “Thymic microenvironments for T-cell repertoire formation,” Advances in Immunology, vol. 99, pp. 59–94, 2008.
- S. Murata, Y. Takahama, and K. Tanaka, “Thymoproteasome: probable role in generating positively selecting peptides,” Current Opinion in Immunology, vol. 20, no. 2, pp. 192–196, 2008.
- M. A. Weinreich and K. A. Hogquist, “Thymic emigration: when and how T cells leave home,” Journal of Immunology, vol. 181, no. 4, pp. 2265–2270, 2008.
- J. Derbinski, A. Schulte, B. Kyewski, and L. Klein, “Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self,” Nature Immunology, vol. 2, no. 11, pp. 1032–1039, 2001.
- M. S. Anderson, E. S. Venanzi, L. Klein et al., “Projection of an immunological self shadow within the thymus by the aire protein,” Science, vol. 298, no. 5597, pp. 1395–1401, 2002.
- R. Bonasio, M. L. Scimone, P. Schaerli, N. Grabie, A. H. Lichtman, and U. H. von Andrian, “Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus,” Nature Immunology, vol. 7, no. 10, pp. 1092–1100, 2006.
- K. Mori, M. Itoi, N. Tsukamoto, H. Kubo, and T. Amagai, “The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma,” International Immunology, vol. 19, no. 6, pp. 745–753, 2007.
- M. Matloubian, C. G. Lo, G. Cinamon et al., “Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1,” Nature, vol. 427, no. 6972, pp. 355–360, 2004.
- M. L. Allende, J. L. Dreier, S. Mandala, and R. L. Proia, “Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration,” Journal of Biological Chemistry, vol. 279, no. 15, pp. 15396–15401, 2004.
- P. J. Fink and D. W. Hendricks, “Post-thymic maturation: young T cells assert their individuality,” Nature Reviews Immunology, vol. 11, no. 8, pp. 544–549, 2011.
- C. W. J. Lio and C. S. Hsieh, “Becoming self-aware: the thymic education of regulatory T cells,” Current Opinion in Immunology, vol. 23, no. 2, pp. 213–219, 2011.
- H. R. Rodewald, S. Paul, C. Haller, H. Bluethmann, and C. Blum, “Thymus medulla consisting of epithelial islets each derived from a single progenitor,” Nature, vol. 414, no. 6865, pp. 763–768, 2001.
- D. L. Mueller, “Mechanisms maintaining peripheral tolerance,” Nature Immunology, vol. 11, no. 1, pp. 21–27, 2010.
- T. Zal, A. Volkmann, and B. Stockinger, “Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen,” Journal of Experimental Medicine, vol. 180, no. 6, pp. 2089–2099, 1994.
- M. Hinterberger, M. Aichinger, O. P. Da Costa, D. Voehringer, R. Hoffmann, and L. Klein, “Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance,” Nature Immunology, vol. 11, no. 6, pp. 512–519, 2010.
- E. Román, H. Shino, F. X. F. Qin, and Y. J. Liu, “Cutting edge: hematopoietic-derived APCs select regulatory T cells in thymus,” Journal of Immunology, vol. 185, no. 7, pp. 3819–3823, 2010.
- A. I. Proietto, S. Van Dommelen, P. Zhou et al., “Dendritic cells in the thymus contribute to T-regulatory cell induction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19869–19874, 2008.
- A. M. Gallegos and M. J. Bevan, “Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation,” Journal of Experimental Medicine, vol. 200, no. 8, pp. 1039–1049, 2004.
- H. Nunes-Cabaço, I. Caramalho, N. Sepúlveda, and A. E. Sousa, “Differentiation of human thymic regulatory T cells at the double positive stage,” European Journal of Immunology, vol. 41, no. 12, pp. 3604–3614, 2011.
- N. Watanabe, S. Hanabuchi, V. Soumelis et al., “Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion,” Nature Immunology, vol. 5, no. 4, pp. 426–434, 2004.
- G. Y. Liu, P. J. Fairchild, R. M. Smith, J. R. Prowle, D. Kioussis, and D. C. Wraith, “Low avidity recognition of self-antigen by T cells permits escape from central tolerance,” Immunity, vol. 3, no. 4, pp. 407–415, 1995.
- A. L. Fletcher, D. Malhotra, and S. J. Turley, “Lymph node stroma broaden the peripheral tolerance paradigm,” Trends in Immunology, vol. 32, no. 1, pp. 12–18, 2011.
- T. C. Metzger and M. S. Anderson, “Control of central and peripheral tolerance by Aire,” Immunological Reviews, vol. 241, no. 1, pp. 89–103, 2011.
- J. M. Gardner, J. J. DeVoss, R. S. Friedman et al., “Deletional tolerance mediated by extrathymic aire-expressing cells,” Science, vol. 321, no. 5890, pp. 843–847, 2008.
- J. N. Cohen, C. J. Guidi, E. F. Tewalt et al., “Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation,” Journal of Experimental Medicine, vol. 207, no. 4, pp. 681–688, 2010.
- L. Yip, L. Su, D. Sheng et al., “Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes,” Nature Immunology, vol. 10, no. 9, pp. 1026–1033, 2009.
- A. L. Fletcher, V. Lukacs-Kornek, E. D. Reynoso et al., “Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions,” Journal of Experimental Medicine, vol. 207, no. 4, pp. 689–697, 2010.
- J. W. Lee, M. Epardaud, J. Sun et al., “Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self,” Nature Immunology, vol. 8, no. 2, pp. 181–190, 2007.
- N. Tokuda, T. Adachi, Y. Adachi et al., “Identification of FABP7 in fibroblastic reticular cells of mouse lymph nodes,” Histochemistry and Cell Biology, vol. 134, no. 5, pp. 445–452, 2010.
- C. C. Clement, O. Rotzschke, and L. Santambrogio, “The lymph as a pool of self-antigens,” Trends in Immunology, vol. 32, no. 1, pp. 6–11, 2011.
- C. C. Clement, E. S. Cannizzo, M. D. Nastke et al., “An expanded self-antigen peptidome is carried by the human lymph as compared to the plasma,” PloS One, vol. 5, no. 3, Article ID e9863, 2010.
- P. Marrack and J. Kappler, “Control of T cell viability,” Annual Review of Immunology, vol. 22, pp. 765–787, 2004.
- V. Benseler, A. Warren, M. Vo et al., “Hepatocyte entry leads to degradation of autoreactive CD8 T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 40, pp. 16735–16740, 2011.
- J. G. Humble, W. H. Jayne, and R. J. Pulvertaft, “Biological interaction between lymphocytes and other cells,” British journal of haematology, vol. 2, no. 3, pp. 283–294, 1956.
- W. H. Lewis, “The engulfment of living blood cells by others of the same type,” The Anatomical Record, vol. 31, no. 1, pp. 43–49, 1925.
- H. Bour-Jordan, J. H. Esensten, M. Martinez-Llordella, C. Penaranda, M. Stumpf, and J. A. Bluestone, “Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family,” Immunological Reviews, vol. 241, no. 1, pp. 180–205, 2011.
- B. S. Reis and D. Mucida, “The role of the intestinal context in the generation of tolerance and inflammation,” Clinical and Developmental Immunology, vol. 2012, Article ID 157948, 6 pages, 2012.
- H. L. Weiner, A. P. da Cunha, F. Quintana, and H. Wu, “Oral tolerance,” Immunological Reviews, vol. 241, no. 1, pp. 241–259, 2011.
- G. B. Olson and B. S. Wostmann, “Lymphocytopoiesis, plasmacytopoiesis and cellular proliferation in nonantigenically stimulated germfree mice,” Journal of Immunology, vol. 97, no. 2, pp. 267–274, 1966.
- W. S. Garrett, J. I. Gordon, and L. H. Glimcher, “Homeostasis and Inflammation in the Intestine,” Cell, vol. 140, no. 6, pp. 859–870, 2010.
- N. A. Bos, C. G. Meeuwsen, B. S. Wostmann, J. R. Pleasants, and R. Benner, “The influence of exogenous antigenic stimulation on the specificity repertoire of background immunoglobulin-secreting cells of different isotypes,” Cellular Immunology, vol. 112, no. 2, pp. 371–380, 1988.
- K. M. Maslowski, A. T. Vieira, A. Ng et al., “Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43,” Nature, vol. 461, no. 7268, pp. 1282–1286, 2009.
- J. da Silva Menezes, D. de Sousa Mucida, D. C. Cara et al., “Stimulation by food proteins plays a critical role in the maturation of the immune system,” International Immunology, vol. 15, no. 3, pp. 447–455, 2003.
- J. F. Amaral, A. C. Gomes-Santos, J. Paula-Silva et al., “Antigenic dietary protein guides maturation of the host immune system promoting resistance to Leishmania major infection in C57BL/6 mice,” Immunology, vol. 129, no. 3, pp. 455–464, 2010.
- D. G. Hanson, N. M. Vaz, L. C. Maia, M. M. Hornbrook, J. M. Lynch, and C. A. Roy, “Inhibition of specific immune responses by feeding protein antigens,” International Archives of Allergy and Applied Immunology, vol. 55, no. 1–6, pp. 526–532, 1977.
- L. K. Richman, J. M. Chiller, and W. R. Brown, “Enterically induced immunologic tolerance. I. Induction of suppressor T lymphocytes by intragastric administration of soluble proteins,” Journal of Immunology, vol. 121, no. 6, pp. 2429–2434, 1978.
- D. Mucida, N. Kutchukhidze, A. Erazo, M. Russo, J. J. Lafaille, and M. A. Curotto De Lafaille, “Oral tolerance in the absence of naturally occurring Tregs,” Journal of Clinical Investigation, vol. 115, no. 7, pp. 1923–1933, 2005.
- L. Mayer and L. Shao, “Therapeutic potential of oral tolerance,” Nature Reviews Immunology, vol. 4, no. 6, pp. 407–419, 2004.
- M. Iwata, A. Hirakiyama, Y. Eshima, H. Kagechika, C. Kato, and S. Y. Song, “Retinoic acid imprints gut-homing specificity on T cells,” Immunity, vol. 21, no. 4, pp. 527–538, 2004.
- J. R. Mora, M. Iwata, B. Eksteen et al., “Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells,” Science, vol. 314, no. 5802, pp. 1157–1160, 2006.
- J. A. Bluestone, “Mechanisms of tolerance,” Immunological Reviews, vol. 241, no. 1, pp. 5–19, 2011.
- J. L. Coombes, K. R. R. Siddiqui, C. V. Arancibia-Cárcamo et al., “A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β -and retinoic acid-dependent mechanism,” Journal of Experimental Medicine, vol. 204, no. 8, pp. 1757–1764, 2007.
- E. Jaensson, H. Uronen-Hansson, O. Pabst et al., “Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans,” Journal of Experimental Medicine, vol. 205, no. 9, pp. 2139–2149, 2008.
- J. M. Kyd and A. W. Cripps, “Functional differences between M cells and enterocytes in sampling luminal antigens,” Vaccine, vol. 26, no. 49, pp. 6221–6224, 2008.
- M. Yoshida, K. Kobayashi, T. T. Kuo et al., “Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria,” Journal of Clinical Investigation, vol. 116, no. 8, pp. 2142–2151, 2006.
- M. Rescigno, “Intestinal dendritic cells,” Advances in Immunology, vol. 107, pp. 109–138, 2010.
- M. Chieppa, M. Rescigno, A. Y. C. Huang, and R. N. Germain, “Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement,” Journal of Experimental Medicine, vol. 203, no. 13, pp. 2841–2852, 2006.
- D. Mucida, Y. Park, G. Kim et al., “Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid,” Science, vol. 317, no. 5835, pp. 256–260, 2007.
- G. Matteoli, E. Mazzini, I. D. Iliev et al., “Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction,” Gut, vol. 59, no. 5, pp. 595–604, 2010.
- M. T. Pallotta, C. Orabona, C. Volpi et al., “Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells,” Nature Immunology, vol. 12, no. 9, pp. 870–878, 2011.
- D. M. Miller, Y. Ogawa, K. K. Iwata et al., “Characterization of the binding of transforming growth factor-β1, -β2, and -β3 to recombinant β1-latency-associated peptide,” Molecular Endocrinology, vol. 6, no. 5, pp. 694–702, 1992.
- A. Awasthi, Y. Carrier, J. P. S. Peron et al., “A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells,” Nature Immunology, vol. 8, no. 12, pp. 1380–1389, 2007.
- M. A. Curotto de Lafaille, N. Kutchukhidze, S. Shen, Y. Ding, H. Yee, and J. J. Lafaille, “Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation,” Immunity, vol. 29, no. 1, pp. 114–126, 2008.
- H. Ochi, M. Abraham, H. Ishikawa et al., “Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25-LAP+ T cells,” Nature Medicine, vol. 12, no. 6, pp. 627–635, 2006.
- F. J. Quintana, G. Murugaiyan, M. F. Farez et al., “An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 48, pp. 20768–20773, 2010.
- L. Apetoh, F. J. Quintana, C. Pot et al., “The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27,” Nature Immunology, vol. 11, no. 9, pp. 854–861, 2010.
- H. L. Weiner, “The mucosal milieu creates tolerogenic dendritic cells and TR l and TH3 regulatory cells,” Nature Immunology, vol. 2, no. 8, pp. 671–672, 2001.
- H. Y. Wu, F. J. Quintana, and H. L. Weiner, “Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+CD25-LAP+ regulatory T Cell and is associated with down-regulation of IL-17+CD4+ICOS+CXCR5+ follicular helper T cells,” Journal of Immunology, vol. 181, no. 9, pp. 6038–6050, 2008.
- A. M. C. Faria and H. L. Weiner, “Oral tolerance: therapeutic implications for autoimmune diseases,” Clinical and Developmental Immunology, vol. 13, no. 2–4, pp. 143–157, 2006.
- O. Akbari, R. H. DeKruyff, and D. T. Umetsu, “Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen,” Nature Immunology, vol. 2, no. 8, pp. 725–731, 2001.
- M. Ostroukhova, C. Seguin-Devaux, T. B. Oriss et al., “Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3,” Journal of Clinical Investigation, vol. 114, no. 1, pp. 28–38, 2004.
- G. Hintzen, L. Ohl, M.-L. Del Rio et al., “Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node,” Journal of Immunology, vol. 177, no. 10, pp. 7346–7354, 2006.
- H. Nakano, M. E. Free, G. S. Whitehead et al., “Pulmonary CD103+ dendritic cells prime Th2 responses to inhaled allergens,” Mucosal Immunology, vol. 5, no. 1, pp. 53–65, 2012.
- J. Zhu, H. Yamane, and W. E. Paul, “Differentiation of effector CD4+ T cell populations,” Annual Review of Immunology, vol. 28, pp. 445–489, 2010.
- R. I. Nurieva, Y. Chung, D. Hwang et al., “Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages,” Immunity, vol. 29, no. 1, pp. 138–149, 2008.
- C. King, S. G. Tangye, and C. R. Mackay, “T follicular helper (TFH) cells in normal and dysregulated immune responses,” Annual Review of Immunology, vol. 26, pp. 741–766, 2008.
- A. Vogelzang, H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King, “A fundamental role for interleukin-21 in the generation of T follicular helper cells,” Immunity, vol. 29, no. 1, pp. 127–137, 2008.
- M. Veldhoen, C. Uyttenhove, J. van Snick et al., “Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,” Nature Immunology, vol. 9, no. 12, pp. 1341–1346, 2008.
- V. Dardalhon, A. Awasthi, H. Kwon et al., “IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3- effector T cells,” Nature Immunology, vol. 9, no. 12, pp. 1347–1355, 2008.
- S. Eyerich, K. Eyerich, D. Pennino et al., “Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling,” Journal of Clinical Investigation, vol. 119, no. 12, pp. 3573–3585, 2009.
- R. M. Locksley, “Nine lives: plasticity among T helper cell subsets,” Journal of Experimental Medicine, vol. 206, no. 8, pp. 1643–1646, 2009.
- C. S. Hsieh, S. E. Macatonia, C. S. Tripp, S. F. Wolf, A. O'Garra, and K. M. Murphy, “Development of T(H)1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages,” Science, vol. 260, no. 5107, pp. 547–549, 1993.
- A. A. Lighvani, D. M. Frucht, D. Jankovic et al., “T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 26, pp. 15137–15142, 2001.
- G. Le Gros, S. Z. Ben-Sasson, R. Seder, F. D. Finkelman, and W. E. Paul, “Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells,” Journal of Experimental Medicine, vol. 172, no. 3, pp. 921–929, 1990.
- S. L. Swain, A. D. Weinberg, M. English, and G. Huston, “IL-4 directs the development of Th2-like helper effectors,” Journal of Immunology, vol. 145, no. 11, pp. 3796–3806, 1990.
- T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009.
- R. A. Flavell, S. Sanjabi, S. H. Wrzesinski, and P. Licona-Limón, “The polarization of immune cells in the tumour environment by TGFβ,” Nature Reviews Immunology, vol. 10, no. 8, pp. 554–567, 2010.
- E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006.
- T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory T H17 cells,” Nature, vol. 448, no. 7152, pp. 484–487, 2007.
- N. Schmitt, R. Morita, L. Bourdery et al., “Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12,” Immunity, vol. 31, no. 1, pp. 158–169, 2009.
- O. Dienz, S. M. Eaton, J. P. Bond et al., “The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells,” Journal of Experimental Medicine, vol. 206, no. 1, pp. 69–78, 2009.
- D. Yu and C. G. Vinuesa, “The elusive identity of T follicular helper cells,” Trends in Immunology, vol. 31, no. 10, pp. 377–383, 2010.
- M. A. Linterman and C. G. Vinuesa, “Signals that influence T follicular helper cell differentiation and function,” Seminars in Immunopathology, vol. 32, no. 2, pp. 183–196, 2010.
- S. J. Szabo, S. T. Kim, G. L. Costa, X. Zhang, C. G. Fathman, and L. H. Glimcher, “A novel transcription factor, T-bet, directs Th1 lineage commitment,” Cell, vol. 100, no. 6, pp. 655–669, 2000.
- A. C. Mullen, F. A. High, A. S. Hutchins et al., “Role of T-bet in commitment of TH1 cells before IL- 12-dependent selection,” Science, vol. 292, no. 5523, pp. 1907–1910, 2001.
- A. C. Mullen, A. S. Hutchins, F. A. High et al., “Hlx is induced by and genetically interacts with T-bet to promote heritable THI gene induction,” Nature Immunology, vol. 3, no. 7, pp. 652–658, 2002.
- B. D. Korman, D. L. Kastner, P. K. Gregersen, and E. F. Remmers, “STAT4: genetics, mechanisms, and implications for autoimmunity,” Current allergy and asthma reports, vol. 8, no. 5, pp. 398–403, 2008.
- A. Balasubramani, Y. Shibata, G. E. Crawford, A. S. Baldwin, R. D. Hatton, and C. T. Weaver, “Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli,” Immunity, vol. 33, no. 1, pp. 35–47, 2010.
- M. Afkarian, J. R. Sedy, J. Yang, et al., “T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells,” Nature Immunology, vol. 3, no. 6, pp. 549–557, 2002.
- W. P. Zheng and R. A. Flavell, “The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells,” Cell, vol. 89, no. 4, pp. 587–596, 1997.
- J. Zhu, B. Min, J. Hu-Li et al., “Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses,” Nature Immunology, vol. 5, no. 11, pp. 1157–1165, 2004.
- S. Y. Pai, M. L. Truitt, and I. C. Ho, “GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 1993–1998, 2004.
- S. Horiuchi, A. Onodera, H. Hosokawa et al., “Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3,” Journal of Immunology, vol. 186, no. 11, pp. 6378–6389, 2011.
- M. D. Siegel, D. H. Zhang, P. Ray, and A. Ray, “Activation of the interleukin-5 promoter by cAMP in murine EL-4 cells requires the GATA-3 and CLE0 elements,” Journal of Biological Chemistry, vol. 270, no. 41, pp. 24548–24555, 1995.
- M. Yamashita, M. Ukai-Tadenuma, M. Kimura et al., “Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus,” Journal of Biological Chemistry, vol. 277, no. 44, pp. 42399–42408, 2002.
- S. Agarwal, O. Avni, and A. Rao, “Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo,” Immunity, vol. 12, no. 6, pp. 643–652, 2000.
- J. Zhu, J. Cote-Sierra, L. Guo, and W. E. Paul, “Stat5 activation plays a critical role in Th2 differentiation,” Immunity, vol. 19, no. 5, pp. 739–748, 2003.
- L. M. Heltemes-Harris, M. J.L. Willette, K. B. Vang, and M. A. Farrar, “The role of STAT5 in the development, function, and transformation of B and T lymphocytes,” Annals of the New York Academy of Sciences, vol. 1217, no. 1, pp. 18–31, 2011.
- M. H. Kaplan, U. Schindler, S. T. Smiley, and M. J. Grusby, “Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells,” Immunity, vol. 4, no. 3, pp. 313–319, 1996.
- H. Takeda, T. Tanaka, W. Shi et al., “Essential role of Stat6 in IL-4 signalling,” Nature, vol. 380, no. 6575, pp. 627–630, 1996.
- J. Zhu, L. Guo, C. J. Watson, J. Hu-Li, and W. E. Paul, “Stat6 is necessary and sufficient for IL-4's role in TH2 differentiation and cell expansion,” Journal of Immunology, vol. 166, no. 12, pp. 7276–7281, 2001.
- N. Van Panhuys, S. C. Tang, M. Prout et al., “In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 34, pp. 12423–12428, 2008.
- Q. Yu, A. Sharma, S. Y. Oh et al., “T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ,” Nature Immunology, vol. 10, no. 9, pp. 992–999, 2009.
- E. Maier, D. Hebenstreit, G. Posselt, P. Hammerl, A. Duschl, and J. Horejs-Hoeck, “Inhibition of suppressive T cell factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling,” Journal of Biological Chemistry, vol. 286, no. 2, pp. 919–928, 2011.
- A. Sahoo, C.-G. Lee, A. Jash et al., “Stat6 and c-Jun mediate Th2 cell-specific IL-24 gene expression,” Journal of Immunology, vol. 186, no. 7, pp. 4098–4109, 2011.
- G. L. Stritesky, R. Muthukrishnan, S. Sehra et al., “The Transcription Factor STAT3 Is Required for T Helper 2 Cell Development,” Immunity, vol. 34, no. 1, pp. 39–49, 2011.
- I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006.
- X. O. Yang, B. P. Pappu, R. Nurieva et al., “T Helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ,” Immunity, vol. 28, no. 1, pp. 29–39, 2008.
- L. A. Solt, N. Kumar, P. Nuhant et al., “Suppression of T H 17 differentiation and autoimmunity by a synthetic ROR ligand,” Nature, vol. 472, no. 7344, pp. 491–494, 2011.
- C. Taflin, B. Favier, J. Baudhuin et al., “Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 7, pp. 2891–2896, 2011.
- L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007.
- R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007.
- X. O. Yang, A. D. Panopoulos, R. Nurieva et al., “STAT3 regulates cytokine-mediated generation of inflammatory helper T cells,” Journal of Biological Chemistry, vol. 282, no. 13, pp. 9358–9363, 2007.
- S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory T cell development by the transcription factor Foxp3,” Science, vol. 299, no. 5609, pp. 1057–1061, 2003.
- J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003.
- M. E. Brunkow, E. W. Jeffery, K. A. Hjerrild et al., “Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse,” Nature Genetics, vol. 27, no. 1, pp. 68–73, 2001.
- C. L. Bennett, J. Christie, F. Ramsdell et al., “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3,” Nature Genetics, vol. 27, no. 1, pp. 20–21, 2001.
- M. A. Gavin, J. P. Rasmussen, J. D. Fontenot et al., “Foxp3-dependent programme of regulatory T-cell differentiation,” Nature, vol. 445, no. 7129, pp. 771–775, 2007.
- S. Z. Josefowicz and A. Rudensky, “Control of Regulatory T Cell Lineage Commitment and Maintenance,” Immunity, vol. 30, no. 5, pp. 616–625, 2009.
- Y. Y. Wan and R. A. Flavell, “Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression,” Nature, vol. 445, no. 7129, pp. 766–770, 2007.
- L. M. Williams and A. Y. Rudensky, “Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3,” Nature Immunology, vol. 8, no. 3, pp. 277–284, 2007.
- M. Feuerer, J. A. Hill, D. Mathis, and C. Benoist, “Foxp3+ regulatory T cells: differentiation, specification, subphenotypes,” Nature Immunology, vol. 10, no. 7, pp. 689–695, 2009.
- W. Lin, D. Haribhai, L. M. Relland et al., “Regulatory T cell development in the absence of functional Foxp3,” Nature Immunology, vol. 8, no. 4, pp. 359–368, 2007.
- J. A. Hill, M. Feuerer, K. Tash et al., “Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature,” Immunity, vol. 27, no. 5, pp. 786–800, 2007.
- A. S. Adamson, K. Collins, A. Laurence, and J. J. O'Shea, “The Current STATus of lymphocyte signaling: new roles for old players,” Current Opinion in Immunology, vol. 21, no. 2, pp. 161–166, 2009.
- T. S. Davidson, R. J. DiPaolo, J. Andersson, and E. M. Shevach, “Cutting edge: IL-2 is essential for TGF-β-mediated induction of Foxp3+ T regulatory cells,” Journal of Immunology, vol. 178, no. 7, pp. 4022–4026, 2007.
- M. A. Burchill, J. Yang, C. Vogtenhuber, B. R. Blazar, and M. A. Farrar, “IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells,” Journal of Immunology, vol. 178, no. 1, pp. 280–290, 2007.
- M. A. Burchill, J. Yang, K. B. Vang et al., “Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire,” Immunity, vol. 28, no. 1, pp. 112–121, 2008.
- Z. Yao, Y. Kanno, M. Kerenyi et al., “Nonredundant roles for Stat5a/b in directly regulating Foxp,” Blood, vol. 109, no. 10, pp. 4368–4375, 2007.
- C. W. J. Lio and C. S. Hsieh, “A two-step process for thymic regulatory T cell development,” Immunity, vol. 28, no. 1, pp. 100–111, 2008.
- D. K. Sojka and D. J. Fowell, “Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 45, pp. 18336–18341, 2011.
- T. Chtanova, S. G. Tangye, R. Newton et al., “T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells,” Journal of Immunology, vol. 173, no. 1, pp. 68–78, 2004.
- D. Yu, S. Rao, L. M. Tsai et al., “The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment,” Immunity, vol. 31, no. 3, pp. 457–468, 2009.
- R. I. Nurieva, Y. Chung, G. J. Martinez et al., “Bcl6 mediates the development of T follicular helper cells,” Science, vol. 325, no. 5943, pp. 1001–1005, 2009.
- R. J. Johnston, A. C. Poholek, D. DiToro et al., “Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation,” Science, vol. 325, no. 5943, pp. 1006–1010, 2009.
- F. Eddahri, S. Denanglaire, F. Bureau et al., “Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities,” Blood, vol. 113, no. 11, pp. 2426–2433, 2009.
- J. Rolf, K. Fairfax, and M. Turner, “Signaling pathways in T follicular helper cells,” Journal of Immunology, vol. 184, no. 12, pp. 6563–6568, 2010.
- G. T. Belz and A. Kallies, “Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination,” Current Opinion in Immunology, vol. 22, no. 3, pp. 279–285, 2010.
- P. A. Shrikant, R. Rao, Q. Li et al., “Regulating functional cell fates in CD8 T cells,” Immunologic Research, vol. 46, no. 1–3, pp. 12–22, 2010.
- N. Zhang and M. Bevan, “CD8+ T Cells: foot Soldiers of the Immune System,” Immunity, vol. 35, no. 2, pp. 161–168, 2011.
- F. Sallusto, D. Lenig, R. Förster, M. Lipp, and A. Lanzavecchia, “Two subsets of memory T lymphocytes with distinct homing potentials and effector functions,” Nature, vol. 401, no. 6754, pp. 708–712, 1999.
- L. Gattinoni, E. Lugli, Y. Ji et al., “A human memory T cell subset with stem cell-like properties,” Nature Medicine, vol. 17, no. 10, pp. 1290–1297, 2011.
- Y. Zhang, G. Joe, E. Hexner, J. Zhu, and S. G. Emerson, “Host-reactive CD8+ memory stem cells in graft-versus-host disease,” Nature Medicine, vol. 11, no. 12, pp. 1299–1305, 2005.
- L. Gattinoni, X. S. Zhong, D. C. Palmer et al., “Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells,” Nature Medicine, vol. 15, no. 7, pp. 808–813, 2009.
- M. Prlic and M. J. Bevan, “Cutting edge: β-catenin is dispensable for T cell effector differentiation, Memory formation, and recall responses,” Journal of Immunology, vol. 187, no. 4, pp. 1542–1546, 2011.
- K. Schepers, E. Swart, J. W. J. Van Heijst et al., “Dissecting T cell lineage relationships by cellular barcoding,” Journal of Experimental Medicine, vol. 205, no. 10, pp. 2309–2318, 2008.
- E. Teixeiro, M. A. Daniels, S. E. Hamilton et al., “Different T cell receptor signals determine CD8+ memory versus effector development,” Science, vol. 323, no. 5913, pp. 502–505, 2009.
- J. T. Chang, V. R. Palanivel, I. Kinjyo et al., “Asymmetric T lymphocyte division in the initiation of adaptive immune responses,” Science, vol. 315, no. 5819, pp. 1687–1691, 2007.
- C. Gerlach, J. W. J. Van Heijst, E. Swart et al., “One naive T cell, multiple fates in CD8+ T cell differentiation,” Journal of Experimental Medicine, vol. 207, no. 6, pp. 1235–1246, 2010.
- C. Stemberger, K. M. Huster, M. Koffler et al., “A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets,” Immunity, vol. 27, no. 6, pp. 985–997, 2007.
- V. Kalia, S. Sarkar, S. Subramaniam, W. N. Haining, K. A. Smith, and R. Ahmed, “Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo,” Immunity, vol. 32, no. 1, pp. 91–103, 2010.
- M. E. Pipkin, J. A. Sacks, F. Cruz-Guilloty, M. G. Lichtenheld, M. J. Bevan, and A. Rao, “Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells,” Immunity, vol. 32, no. 1, pp. 79–90, 2010.
- J. Chang, M. Ciocca, I. Kinjyo et al., “Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division,” Immunity, vol. 34, no. 4, pp. 492–504, 2011.
- S. J. Szabo, B. M. Sullivan, C. Sternmann, A. R. Satoskar, B. P. Sleckman, and L. H. Glimcher, “Distinct effects of T-bet in Th1 lineage commitment and IFN-γ production in CD4 and CD8 T cells,” Science, vol. 295, no. 5553, pp. 338–342, 2002.
- C. J. J. Yeo and D. T. Fearon, “T-bet-mediated differentiation of the activated CD8+ T cell,” European Journal of Immunology, vol. 41, no. 1, pp. 60–66, 2011.
- M. Heffner and D. T. Fearon, “Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 33, pp. 13414–13419, 2007.
- E. L. Pearce, A. C. Mullen, G. A. Martins et al., “Control of effector CD8+ T cell function by the transcription factor eomesodermin,” Science, vol. 302, no. 5647, pp. 1041–1043, 2003.
- A. Banerjee, S. M. Gordon, A. M. Intlekofer et al., “Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche,” Journal of Immunology, vol. 185, no. 9, pp. 4988–4992, 2010.
- N. S. Joshi, W. Cui, A. Chandele et al., “Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor,” Immunity, vol. 27, no. 2, pp. 281–295, 2007.
- A. M. Intlekofer, N. Takemoto, C. Kao et al., “Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells,” Journal of Experimental Medicine, vol. 204, no. 9, pp. 2015–2021, 2007.
- R. L. Rutishauser, G. A. Martins, S. Kalachikov et al., “Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties,” Immunity, vol. 31, no. 2, pp. 296–308, 2009.
- A. Kallies, A. Xin, G. T. Belz, and S. L. Nutt, “Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses,” Immunity, vol. 31, no. 2, pp. 283–295, 2009.
- A. Xin, S. L. Nutt, G. T. Belz, and A. Kallies, “Blimp1: driving terminal differentiation to a T,” Advances in Experimental Medicine and Biology, vol. 780, pp. 85–100, 2011.
- S. Crotty, R. J. Johnston, and S. P. Schoenberger, “Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation,” Nature Immunology, vol. 11, no. 2, pp. 114–120, 2010.
- H. Shin, S. D. Blackburn, A. M. Intlekofer et al., “A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection,” Immunity, vol. 31, no. 2, pp. 309–320, 2009.
- P. Tripathi, S. Kurtulus, S. Wojciechowski et al., “STAT5 is critical to maintain effector CD8+T cell responses,” Journal of Immunology, vol. 185, no. 4, pp. 2116–2124, 2010.
- T. W. Hand, W. Cui, Y. W. Jung et al., “Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 38, pp. 16601–16606, 2010.
- K. V. Anderson, L. Bokla, and C. Nusslein-Volhard, “Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product,” Cell, vol. 42, no. 3, pp. 791–798, 1985.
- K. V. Anderson, G. Jurgens, and C. Nusslein-Volhard, “Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product,” Cell, vol. 42, no. 3, pp. 779–789, 1985.
- B. Lemaitre, E. Nicolas, L. Michaut, J. M. Reichhart, and J. A. Hoffmann, “The dorsoventral regulatory gene cassette spatzle/Toll/Cactus controls the potent antifungal response in Drosophila adults,” Cell, vol. 86, no. 6, pp. 973–983, 1996.
- C. Chiang and P. A. Beachy, “Expression of a novel Toll-like gene spans the parasegment boundary and contributes to hedgehog function in the adult eye of Drosophila,” Mechanisms of Development, vol. 47, no. 3, pp. 225–239, 1994.
- F. L. Rock, G. Hardiman, J. C. Timans, R. A. Kastelein, and J. F. Bazan, “A family of human receptors structurally related to Drosophila Toll,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 2, pp. 588–593, 1998.
- T. Kawai and S. Akira, “The role of pattern-recognition receptors in innate immunity: update on toll-like receptors,” Nature Immunology, vol. 11, no. 5, pp. 373–384, 2010.
- Z. L. Chang, “Important aspects of Toll-like receptors, ligands and their signaling pathways,” Inflammation Research, vol. 59, no. 10, pp. 791–808, 2010.
- A. I. Tukhvatulin, D. Y. Logunov, D. N. Shcherbinin et al., “Toll-like receptors and their adapter molecules,” Biochemistry, vol. 75, no. 9, pp. 1098–1114, 2010.
- S. Carpenter and L. A. J. O'Neill, “Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins,” Biochemical Journal, vol. 422, no. 1, pp. 1–10, 2009.
- A. L. Blasius and B. Beutler, “Intracellular Toll-like receptors,” Immunity, vol. 32, no. 3, pp. 305–315, 2010.
- A. F. McGettrick and L. A. O'Neill, “Localisation and trafficking of Toll-like receptors: an important mode of regulation,” Current Opinion in Immunology, vol. 22, no. 1, pp. 20–27, 2010.
- S. E. Ewald, B. L. Lee, L. Lau et al., “The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor,” Nature, vol. 456, no. 7222, pp. 658–662, 2008.
- C. A. Leifer, J. C. Brooks, K. Hoelzer et al., “Cytoplasmic targeting motifs control localization of toll-like receptor 9,” Journal of Biological Chemistry, vol. 281, no. 46, pp. 35585–35592, 2006.
- T. Nishiya, E. Kajita, S. Miwa, and A. L. DeFranco, “TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements,” Journal of Biological Chemistry, vol. 280, no. 44, pp. 37107–37117, 2005.
- B. Park, M. M. Brinkmann, E. Spooner, C. C. Lee, Y. M. Kim, and H. L. Ploegh, “Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9,” Nature Immunology, vol. 9, no. 12, pp. 1407–1414, 2008.
- A. Chockalingam, J. C. Brooks, J. L. Cameron, L. K. Blum, and C. A. Leifer, “TLR9 traffics through the Golgi complex to localize to endolysosomes and respond to CpG DNA,” Immunology and Cell Biology, vol. 87, no. 3, pp. 209–217, 2009.
- Y. M. Kim, M. M. Brinkmann, M. E. Paquet, and H. L. Ploegh, “UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes,” Nature, vol. 452, no. 7184, pp. 234–238, 2008.
- M. M. Brinkmann, E. Spooner, K. Hoebe, B. Beutler, H. L. Ploegh, and Y. M. Kim, “The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling,” Journal of Cell Biology, vol. 177, no. 2, pp. 265–275, 2007.
- R. Fukui, S. I. Saitoh, F. Matsumoto et al., “Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing,” Journal of Experimental Medicine, vol. 206, no. 6, pp. 1339–1350, 2009.
- K. Tabeta, K. Hoebe, E. M. Janssen et al., “The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9,” Nature Immunology, vol. 7, no. 2, pp. 156–164, 2006.
- S. Bauer, T. Müller, and S. Hamm, “Pattern recognition by Toll-like receptors,” Advances in experimental medicine and biology, vol. 653, pp. 15–34, 2009.
- H. Wesche, W. J. Henzel, W. Shillinglaw, S. Li, and Z. Cao, “MyD88: an adapter that recruits IRAK to the IL-1 receptor complex,” Immunity, vol. 7, no. 6, pp. 837–847, 1997.
- H. Oshiumi, M. Matsumoto, K. Funami, T. Akazawa, and T. Seya, “TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction,” Nature Immunology, vol. 4, no. 2, pp. 161–167, 2003.
- M. Yamamoto, S. Sato, K. Mori et al., “Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling,” Journal of Immunology, vol. 169, no. 12, pp. 6668–6672, 2002.
- T. Horng, G. M. Barton, and R. Medzhitov, “TIRAP: an adapter molecule in the Toll signaling pathway,” Nature Immunology, vol. 2, no. 9, pp. 835–841, 2001.
- K. A. Fitzgerald, E. M. Palsson-Mcdermott, A. G. Bowie et al., “Mal (MyD88-adapter-like) is required for toll-like recepfor-4 signal transduction,” Nature, vol. 413, no. 6851, pp. 78–83, 2001.
- M. Yamamoto, S. Sato, H. Hemmi et al., “TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway,” Nature Immunology, vol. 4, no. 11, pp. 1144–1150, 2003.
- P. Gray, A. Dunne, C. Brikos, C. A. Jefferies, S. L. Doyle, and L. A. J. O'Neill, “MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction,” Journal of Biological Chemistry, vol. 281, no. 15, pp. 10489–10495, 2006.
- N. Suzuki, S. Suzuki, G. S. Duncan et al., “Severe impairment of interleukin-1 and toll-like receptor signalling in mice lacking IRAK-4,” Nature, vol. 416, no. 6882, pp. 750–754, 2002.
- T. Kawagoe, S. Sato, K. Matsushita et al., “Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2,” Nature Immunology, vol. 9, no. 6, pp. 684–691, 2008.
- M. Muzio, G. Natoli, S. Saccani, M. Levrero, and A. Mantovani, “The human toll signaling pathway: divergence of nuclear factor κb and jnk/sapk activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6),” Journal of Experimental Medicine, vol. 187, no. 12, pp. 2097–2101, 1998.
- F. Tokunaga, S. I. Sakata, Y. Saeki et al., “Involvement of linear polyubiquitylation of NEMO in NF-κB activation,” Nature Cell Biology, vol. 11, no. 2, pp. 123–132, 2009.
- S. Rahighi, F. Ikeda, M. Kawasaki et al., “Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation,” Cell, vol. 136, no. 6, pp. 1098–1109, 2009.
- T. D. Prickett, J. Ninomiya-Tsuji, P. Broglie et al., “TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-κB,” Journal of Biological Chemistry, vol. 283, no. 28, pp. 19245–19254, 2008.
- G. Jin, A. Klika, M. Callahan et al., “Identification of a human NF-κB-activating protein, TAB3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 2028–2033, 2004.
- A. Takaoka, H. Yanai, S. Kondo et al., “Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors,” Nature, vol. 434, no. 7030, pp. 243–249, 2005.
- H. Negishi, Y. Ohba, H. Yanai et al., “Negative regulation of Toll-like-receptor signaling by IRF-4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 44, pp. 15989–15994, 2005.
- P. H. Tseng, A. Matsuzawa, W. Zhang, T. Mino, D. A. A. Vignali, and M. Karin, “Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type i interferons and proinflammatory cytokines,” Nature Immunology, vol. 11, no. 1, pp. 70–75, 2010.
- H. Häcker, V. Redecke, B. Blagoev et al., “Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6,” Nature, vol. 439, no. 7073, pp. 204–207, 2006.
- G. Oganesyan, S. K. Saha, B. Guo et al., “Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response,” Nature, vol. 439, no. 7073, pp. 208–211, 2006.
- K. Honda, Y. Ohba, H. Yanai et al., “Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction,” Nature, vol. 434, no. 7036, pp. 1035–1040, 2005.
- K. Honda, H. Yanai, H. Negishi et al., “IRF-7 is the master regulator of type-I interferon-dependent immune responses,” Nature, vol. 434, no. 7034, pp. 772–777, 2005.
- C. Guiducci, C. Ghirelli, M. A. Marloie-Provost et al., “PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation,” Journal of Experimental Medicine, vol. 205, no. 2, pp. 315–322, 2008.
- I. Zanoni and F. Granucci, “Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors,” Journal of Molecular Medicine, vol. 88, no. 9, pp. 873–880, 2010.
- N. Kadowaki, S. Ho, S. Antonenko et al., “Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens,” Journal of Experimental Medicine, vol. 194, no. 6, pp. 863–869, 2001.
- M. Muzio, D. Bosisio, N. Polentarutti et al., “Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells,” Journal of Immunology, vol. 164, no. 11, pp. 5998–6004, 2000.
- A. Krug, A. Towarowski, S. Britsch et al., “Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with Cd40 ligand to induce high amounts of IL-12,” European Journal of Immunology, vol. 31, no. 10, pp. 3026–3037, 2001.
- V. Hornung, S. Rothenfusser, S. Britsch et al., “Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides,” Journal of Immunology, vol. 168, no. 9, pp. 4531–4537, 2002.
- D. Schattenberg, M. Schott, G. Reindl et al., “Response of human monocyte-derived dendritic cells to immunostimulatory DNA,” European Journal of Immunology, vol. 30, no. 10, pp. 2824–2831, 2000.
- A. D. Edwards, S. S. Diebold, E. M.C. Slack et al., “Toll-like receptor expression in murine DC subsets: lack of TLR7 expresion of CD8α+ DC correlates with unresponsiveness to imidazoquinolines,” European Journal of Immunology, vol. 33, no. 4, pp. 827–833, 2003.
- T. Seya, H. Shime, T. Ebihara, H. Oshiumi, and M. Matsumoto, “Pattern recognition receptors of innate immunity and their application to tumor immunotherapy,” Cancer Science, vol. 101, no. 2, pp. 313–320, 2010.
- M. Chang, W. Jin, and S. C. Sun, “Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production,” Nature Immunology, vol. 10, no. 10, pp. 1089–1095, 2009.
- N. Cusson-Hermance, S. Khurana, T. H. Lee, K. A. Fitzgerald, and M. A. Kelliher, “Rip1 mediates the trif-dependent Toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation,” Journal of Biological Chemistry, vol. 280, no. 44, pp. 36560–36566, 2005.
- B. Jin, T. Sun, X.-H. Yu et al., “Immunomodulatory effects of dsRNA and its potential as vaccine adjuvant,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 690438, 17 pages, 2010.
- M. Sasai, H. Oshiumi, M. Matsumoto et al., “Cutting edge: NF-κB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation,” Journal of Immunology, vol. 174, no. 1, pp. 27–30, 2005.
- W. J. Kaiser and M. K. Offermann, “Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif,” Journal of Immunology, vol. 174, no. 8, pp. 4942–4952, 2005.
- E. Vercammen, J. Staal, and R. Beyaert, “Sensing of viral infection and activation of innate immunity by toll-like receptor 3,” Clinical Microbiology Reviews, vol. 21, no. 1, pp. 13–25, 2008.
- K. J. Han, Y. Yang, L. G. Xu, and H. B. Shu, “Analysis of a TIR-less splice variant of TRIF reveals an unexpected mechanism of TLR3-mediated signaling,” Journal of Biological Chemistry, vol. 285, no. 17, pp. 12543–12550, 2010.
- S. N. Sarkar, K. L. Peters, C. P. Elco, S. Sakamoto, S. Pal, and G. C. Sen, “Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling,” Nature Structural and Molecular Biology, vol. 11, no. 11, pp. 1060–1067, 2004.
- S. N. Sarkar, C. P. Elco, K. L. Peters, S. Chattopadhyay, and G. C. Sen, “Two tyrosine residues of toll-like receptor 3 trigger different steps of NF-κB activation,” Journal of Biological Chemistry, vol. 282, no. 6, pp. 3423–3427, 2007.
- I. B. Johnsen, T. T. Nguyen, M. Ringdal et al., “Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling,” EMBO Journal, vol. 25, no. 14, pp. 3335–3346, 2006.
- G. Liu, L. Zhang, and Y. Zhao, “Modulation of immune responses through direct activation of Toll-like receptors to T cells,” Clinical and Experimental Immunology, vol. 160, no. 2, pp. 168–175, 2010.
- O. Takeuchi and S. Akira, “Innate immunity to virus infection,” Immunological Reviews, vol. 227, no. 1, pp. 75–86, 2009.
- Q. Lin, C. Dong, and M. D. Cooper, “Impairment of T and B cell development by treatment with a type I interferon,” Journal of Experimental Medicine, vol. 187, no. 1, pp. 79–87, 1998.
- T. Tsukiyama, N. Ishida, M. Shirane et al., “Down-regulation of p27Kip1 expression is required for development and function of T cells,” Journal of Immunology, vol. 166, no. 1, pp. 304–312, 2001.
- M.-L. Baron, D. Gauchat, R. L. Motte-Mohs et al., “TLR ligand-induced type I IFNs affect thymopoiesis,” Journal of Immunology, vol. 180, no. 11, pp. 7134–7146, 2008.
- T. Démoulins, A. Abdallah, N. Kettaf et al., “Reversible blockade of thymic output: an inherent part of TLR ligand-mediated immune response,” Journal of Immunology, vol. 181, no. 10, pp. 6757–6769, 2008.
- D. Anz, R. Thaler, N. Stephan et al., “Activation of melanoma differentiation-associated gene 5 causes rapid involution of the thymus,” Journal of Immunology, vol. 182, no. 10, pp. 6044–6050, 2009.
- M. J. Billard, A. L. Gruver, and G. D. Sempowski, “Acute endotoxin-induced thymic atrophy is characterized by intrathymic inflammatory and wound healing responses,” PLoS One, vol. 6, no. 3, Article ID e17940, 2011.
- T. Kawai and S. Akira, “Toll-like receptors and their crosstalk with other innate receptors in infection and immunity,” Immunity, vol. 34, no. 5, pp. 637–650, 2011.
- M. L. Salem, “Triggering of toll-like receptor signaling pathways in T cells contributes to the anti-tumor efficacy of T cell responses,” Immunology Letters, vol. 137, no. 1-2, pp. 9–14, 2011.
- R. Kulkarni, S. Behboudi, and S. Sharif, “Insights into the role of Toll-like receptors in modulation of T cell responses,” Cell and Tissue Research, vol. 343, no. 1, pp. 141–152, 2011.
- K. A. Zarember and P. J. Godowski, “Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines,” Journal of Immunology, vol. 168, no. 2, pp. 554–561, 2002.
- S. E. Applequist, R. P. A. Wallin, and H. G. Ljunggren, “Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines,” International Immunology, vol. 14, no. 9, pp. 1065–1074, 2002.
- M. Komai-Koma, L. Jones, G. S. Ogg, D. Xu, and F. Y. Liew, “TLR2 is expressed activated T cells as a costimulatory receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 3029–3034, 2004.
- M. Schnare, G. M. Barton, A. C. Holt, K. Takeda, S. Akira, and R. Medzhitov, “Toll-like receptors control activation of adaptive immune responses,” Nature Immunology, vol. 2, no. 10, pp. 947–950, 2001.
- S. Bauer, D. Hangel, and P. Yu, “Immunobiology of toll-like receptors in allergic disease,” Immunobiology, vol. 212, no. 6, pp. 521–533, 2007.
- D. E. Gaddis, S. M. Michalek, and J. Katz, “TLR4 signaling via MyD88 and TRIF differentially shape the CD4+ T cell response to Porphyromonas gingivalis hemagglutinin B,” Journal of Immunology, vol. 186, no. 10, pp. 5772–5783, 2011.
- A. F. Heiseke, A. C. Faul, H. Lehr et al., “CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cellmediated protection from colitis,” Gastroenterology, vol. 142, no. 2, pp. 335–345, 2012.
- J. Sun and E. J. Pearce, “Suppression of early IL-4 production underlies the failure of CD4 T cells activated by TLR-stimulated dendritic cells to differentiate into Th2 cells,” Journal of Immunology, vol. 178, no. 3, pp. 1635–1644, 2007.
- S. C. Eisenbarth, D. A. Piggott, J. W. Huleatt, I. Visintin, C. A. Herrick, and K. Bottomly, “Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen,” Journal of Experimental Medicine, vol. 196, no. 12, pp. 1645–1651, 2002.
- D.-H. Kim, J.-C. Lee, S. Kim et al., “Inhibition of autoimmune diabetes by TLR2 tolerance,” Journal of Immunology, vol. 187, no. 10, pp. 5211–5220, 2011.
- J. Patenaude, M. D'Elia, G. Côté-Maurais, and J. Bernier, “LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells,” Cellular Immunology, vol. 271, no. 1, pp. 184–191, 2011.
- M. Schmaler, N. J. Jann, F. Ferracin, and R. Landmann, “T and B cells are not required for clearing Staphylococcus aureus in systemic infection despite a strong TLR2-MyD88-dependent T cell activation,” Journal of Immunology, vol. 186, no. 1, pp. 443–452, 2011.
- M. H. Wenink, K. C. M. Santegoets, J. C. A. Broen et al., “TLR2 promotes Th2/Th17 responses via TLR4 and TLR7/8 by abrogating the Type I IFN amplification loop,” Journal of Immunology, vol. 183, no. 11, pp. 6960–6970, 2009.
- C. Pasare and R. Medzhitov, “Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells,” Science, vol. 299, no. 5609, pp. 1033–1036, 2003.
- D. Hackl, J. Loschko, T. Sparwasser, W. Reindl, and A. B. Krug, “Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs,” European Journal of Immunology, vol. 41, no. 5, pp. 1334–1343, 2011.
- L. Pham Van, E. Bardel, S. Gregoire et al., “Treatment with the TLR7 agonist R848 induces regulatory T-cell-mediated suppression of established asthma symptoms,” European Journal of Immunology, vol. 41, no. 7, pp. 1992–1999, 2011.
- A. Boonstra, C. Asselin-Paturel, M. Gilliet et al., “Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation,” Journal of Experimental Medicine, vol. 197, no. 1, pp. 101–109, 2003.
- S. R. Myneni, R. P. Settem, T. D. Connell, A. D. Keegan, S. L. Gaffen, and A. Sharma, “TLR2 signaling and Th2 responses drive Tannerella forsythia-induced periodontal bone loss,” Journal of Immunology, vol. 187, no. 1, pp. 501–509, 2011.
- J. P. McAleer and A. T. Vella, “Educating CD4 T cells with vaccine adjuvants: lessons from lipopolysaccharide,” Trends in Immunology, vol. 31, no. 11, pp. 429–435, 2010.
- M. N. Alonso, M. T. Wong, A. L. Zhang et al., “T H1, T H2, and T H17 cells instruct monocytes to differentiate into specialized dendritic cell subsets,” Blood, vol. 118, no. 12, pp. 3311–3320, 2011.
- L. L. Lanier, “DAP10- and DAP12-associated receptors in innate immunity,” Immunological Reviews, vol. 227, no. 1, pp. 150–160, 2009.
- C.-L. Chu, Y.-L. Yu, K.-Y. Shen, C. A. Lowell, L. L. Lanier, and J. A. Hamerman, “Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRγ,” European Journal of Immunology, vol. 38, no. 1, pp. 166–173, 2008.
- W. Cao, D. B. Rosen, T. Ito et al., “Plasmacytoid dendritic cell-specific receptor ILT7-FcεRIγ inhibits Toll-like receptor-induced interferon production,” Journal of Experimental Medicine, vol. 203, no. 6, pp. 1399–1405, 2006.
- H. Ito and J. A. Hamerman, “TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells,” European Journal of Immunology, vol. 42, no. 1, pp. 176–185, 2012.
- A. H. Rahman, D. K. Taylor, and L. A. Turka, “The contribution of direct TLR signaling to T cell responses,” Immunologic Research, vol. 45, no. 1, pp. 25–36, 2009.
- V. Sobek, N. Birkner, I. Falk et al., “Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease,” Arthritis Research & Therapy, vol. 6, no. 5, pp. R433–446, 2004.
- A. E. Gelman, J. Zhang, Y. Choi, and L. A. Turka, “Toll-like receptor ligands directly promote activated CD4+ T cell survival,” Journal of Immunology, vol. 172, no. 10, pp. 6065–6073, 2004.
- H. Liu, M. Komai-Koma, D. Xu, and F. Y. Liew, “Toll-like receptor 2 signaling modulates the functions of CD4+CD25+ regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 18, pp. 7048–7053, 2006.
- C. L. Lancioni, J. J. Thomas, and R. E. Rojas, “Activation requirements and responses to TLR ligands in human CD4+ T cells: comparison of two T cell isolation techniques,” Journal of Immunological Methods, vol. 344, no. 1, pp. 15–25, 2009.
- A. Cottalorda, C. Verschelde, A. Marçais et al., “TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation,” European Journal of Immunology, vol. 36, no. 7, pp. 1684–1693, 2006.
- B. C. Mercier, A. Cottalorda, C. A. Coupet, J. Marvel, and N. Bonnefoy-Bérard, “TLR2 engagement on CD8 T cells enables generation of functional memory cells in response to a suboptimal TCR signal,” Journal of Immunology, vol. 182, no. 4, pp. 1860–1867, 2009.
- A. Cottalorda, B. C. Mercier, F. M. Mbitikon-Kobo et al., “TLR2 engagement on memory CD8+ T cells improves their cytokine-mediated proliferation and IFN-γ secretion in the absence of Ag,” European Journal of Immunology, vol. 39, no. 10, pp. 2673–2681, 2009.
- M. Quigley, J. Martinez, X. Huang, and Y. Yang, “A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection,” Blood, vol. 113, no. 10, pp. 2256–2264, 2009.
- A. E. Gelman, D. F. LaRosa, J. Zhang et al., “The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation,” Immunity, vol. 25, no. 5, pp. 783–793, 2006.
- C. K. Holm, C. C. Petersen, M. Hvid et al., “TLR3 ligand polyinosinic: polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells,” Journal of Immunology, vol. 183, no. 7, pp. 4422–4431, 2009.
- R. P. M. Sutmuller, M. H. M. G. M. Den Brok, M. Kramer et al., “Toll-like receptor 2 controls expansion and function of regulatory T cells,” Journal of Clinical Investigation, vol. 116, no. 2, pp. 485–494, 2006.
- H. H. Oberg, T. T. H. Ly, S. Ussat, T. Meyer, D. Kabelitz, and D. Wesch, “Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands,” Journal of Immunology, vol. 184, no. 9, pp. 4733–4740, 2010.
- Y. G. Tsai, K. D. Yang, D. M. Niu, J. W. Chien, and C. Y. Lin, “TLR2 agonists enhance CD8+Foxp3+ regulatory T cells and suppress Th2 immune responses during allergen immunotherapy,” Journal of Immunology, vol. 184, no. 12, pp. 7229–7237, 2010.
- W. W.C. van Maren, S. Nierkens, L. W. Toonen, J. M. Bolscher, R. P.M. Sutmuller, and G. J. Adema, “Multifaceted effects of synthetic TLR2 ligand and Legionella pneumophilia on Treg-mediated suppression of T cell activation,” BMC Immunology, vol. 12, article 23, 2011.
- J. M. Reynolds, B. P. Pappu, J. Peng et al., “Toll-like receptor 2 signaling in CD4+ T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease,” Immunity, vol. 32, no. 5, pp. 692–702, 2010.
- M. H. Nyirenda, L. Sanvito, P. J. Darlington et al., “TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function,” Journal of Immunology, vol. 187, no. 5, pp. 2278–2290, 2011.
- M. D. Sharma, D. Y. Hou, B. Baban et al., “Reprogrammed Foxp3+ regulatory T cells provide essential help to support cross-presentation and CD8+ T cell priming in naive mice,” Immunity, vol. 33, no. 6, pp. 942–954, 2010.
- A. L. Mellor and D. H. Munn, “Physiologic control of the functional status of Foxp3+ regulatory T cells,” Journal of Immunology, vol. 186, no. 8, pp. 4535–4540, 2011.
- X. O. Yang, R. Nurieva, G. J. Martinez et al., “Molecular antagonism and plasticity of regulatory and inflammatory T cell programs,” Immunity, vol. 29, no. 1, pp. 44–56, 2008.
- L. Li, J. Kim, and V. A. Boussiotis, “IL-1β-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells,” Journal of Immunology, vol. 185, no. 7, pp. 4148–4153, 2010.
- R. P. M. Sutmuller, M. E. Morgan, M. G. Netea, O. Grauer, and G. J. Adema, “Toll-like receptors on regulatory T cells: expanding immune regulation,” Trends in Immunology, vol. 27, no. 8, pp. 387–393, 2006.
- Y. Zhang, F. Luo, Y. Cai et al., “TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells,” Journal of Immunology, vol. 186, no. 4, pp. 1963–1969, 2011.
- A. Zanin-Zhorov, L. Cahalon, G. Tal, R. Margalit, O. Lider, and I. R. Cohen, “Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 2022–2032, 2006.
- I. De Kleer, Y. Vercoulen, M. Klein et al., “CD30 discriminates heat shock protein 60-induced FOXP3+ CD4+ T cells with a regulatory phenotype,” Journal of Immunology, vol. 185, no. 4, pp. 2071–2079, 2010.
- C. A. Wild, S. Brandau, M. Lindemann et al., “Toll-like receptors in regulatory T cells of patients with head and neck cancer,” Archives of Otolaryngology - Head and Neck Surgery, vol. 136, no. 12, pp. 1253–1259, 2010.
- I. Caramalho, T. Lopes-Carvalho, D. Ostler, S. Zelenay, M. Haury, and J. Demengeot, “Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide,” Journal of Experimental Medicine, vol. 197, no. 4, pp. 403–411, 2003.
- P. Lewkowicz, N. Lewkowicz, A. Sasiak, and H. Tchórzewski, “Lipopolysaccharide-activated CD4+CD25+ T regulatory cells inhibit neutrophil function and promote their apoptosis and death,” Journal of Immunology, vol. 177, no. 10, pp. 7155–7163, 2006.
- N. K. Crellin, R. V. Garcia, O. Hadisfar, S. E. Allan, T. S. Steiner, and M. K. Levings, “Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells,” Journal of Immunology, vol. 175, no. 12, pp. 8051–8059, 2005.
- D. Kabelitz, “Expression and function of Toll-like receptors in T lymphocytes,” Current Opinion in Immunology, vol. 19, no. 1, pp. 39–45, 2007.
- G. Peng, Z. Guo, Y. Kiniwa et al., “Immunology: Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function,” Science, vol. 309, no. 5739, pp. 1380–1384, 2005.
- D. F. LaRosa, A. E. Gelman, A. H. Rahman, J. Zhang, L. A. Turka, and P. T. Walsh, “CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells,” Immunology Letters, vol. 108, no. 2, pp. 183–188, 2007.
- B. Baban, P. R. Chandler, M. D. Sharma et al., “IDO activates regulatory T cells and blocks their conversion into Th17-like T cells,” Journal of Immunology, vol. 183, no. 4, pp. 2475–2483, 2009.
- M. D. Sharma, D. Y. Hou, Y. Liu et al., “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009.
- M. Tsuji, N. Komatsu, S. Kawamoto et al., “Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches,” Science, vol. 323, no. 5920, pp. 1488–1492, 2009.
- Y. Wang, A. Souabni, R. A. Flavell, and Y. Y. Wan, “An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo,” Journal of Immunology, vol. 185, no. 10, pp. 5983–5992, 2010.
- S. Vendetti, T. S. Davidson, F. Veglia et al., “Polyclonal Treg cells enhance the activity of a mucosal adjuvant,” Immunology and Cell Biology, vol. 88, no. 7, pp. 698–706, 2010.
- J. W. Yewdell, “Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses,” Immunity, vol. 25, no. 4, pp. 533–543, 2006.
- S. Siddiqui and S. Basta, “CD8+ T cell immunodominance in lymphocytic choriomeningitis virus infection is modified in the presence of toll-like receptor agonists,” Journal of Virology, vol. 85, no. 24, pp. 13224–13233, 2011.
- J. Magarian Blander and R. Medzhitov, “Toll-dependent selection of microbial antigens for presentation by dendritic cells,” Nature, vol. 440, no. 7085, pp. 808–812, 2006.
- H. T. Ichikawa, L. P. Williams, and B. M. Segal, “Activation of APCs through CD40 or toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease,” Journal of Immunology, vol. 169, no. 5, pp. 2781–2787, 2002.
- Y. Liu, X. Tian, W. W. Leitner et al., “Polymeric structure and host toll-like receptor 4 dictate immunogenicity of NY-ESO-1 antigen in vivo,” Journal of Biological Chemistry, vol. 286, no. 43, pp. 37077–37084, 2011.
- A. C.C. Lin, D. Dissanayake, S. Dhanji, A. R. Elford, and P. S. Ohashi, “Different toll-like receptor stimuli have a profound impact on cytokines required to break tolerance and induce autoimmunity,” PLoS One, vol. 6, no. 9, Article ID e23940, 2011.
- S. Chiesa, S. Morbelli, S. Morando et al., “Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 42, pp. 17384–17389, 2011.
- S. Nierkens, M. H. Den Brok, Z. Garcia et al., “Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells,” Cancer Research, vol. 71, no. 20, pp. 6428–6437, 2011.
- E. Shklovskaya, B. J. O'Sullivan, L. G. Ng et al., “Langerhans cells are precommitted to immune tolerance induction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 44, pp. 18049–18054, 2011.
- A. M.G. Van Der Aar, R. De Groot, M. Sanchez-Hernandez et al., “Cutting edge: virus selectively primes human Langerhans cells for CD70 expression promoting CD8+ T cell responses,” Journal of Immunology, vol. 187, no. 7, pp. 3488–3492, 2011.
- K. Fujimoto, T. Karuppuchamy, N. Takemura et al., “A new subset of CD103+CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity,” Journal of Immunology, vol. 186, no. 11, pp. 6287–6295, 2011.
- C. Reis E Sousa, “Dendritic cells in a mature age,” Nature Reviews Immunology, vol. 6, no. 6, pp. 476–483, 2006.
- J. Valencia, C. Hernández-López, V. G. Martínez et al., “Wnt5a skews dendritic cell differentiation to an unconventional phenotype with tolerogenic features,” Journal of Immunology, vol. 187, no. 8, pp. 4129–4139, 2011.
- E. E. Hamilton-Williams, A. Lang, D. Benke, G. M. Davey, K.-H. Wiesmüller, and C. Kurts, “Cutting edge: TLR ligands are not sufficient to break cross-tolerance to self-antigens,” Journal of Immunology, vol. 174, no. 3, pp. 1159–1163, 2005.
- C. G. King, T. Kobayashi, P. J. Cejas et al., “TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis,” Nature Medicine, vol. 12, no. 9, pp. 1088–1092, 2006.
- S. N. Mueller, M. Matloubian, D. M. Clemens et al., “Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 39, pp. 15430–15435, 2007.
- M. E. Mendes, G. L. Baggio-Zappia, M. K. C. Brunialti, M. D. L. Fernandes, M. M. Rapozo, and R. Salomao, “Differential expression of toll-like receptor signaling cascades in LPS-tolerant human peripheral blood mononuclear cells,” Immunobiology, vol. 216, no. 3, pp. 285–295, 2011.
- S. M. Mangsbo, L. C. Sandin, K. Anger, A. J. Korman, A. Loskog, and T. H. Tötterman, “Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy,” Journal of Immunotherapy, vol. 33, no. 3, pp. 225–235, 2010.
- J. M. Wells, O. Rossia, M. Meijerink, and P. Van Baarlen, “Epithelial crosstalk at the microbiota-mucosal interface,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. SUPPL. 1, pp. 4607–4614, 2011.
- M. T. Abreu, “Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function,” Nature Reviews Immunology, vol. 10, no. 2, pp. 131–143, 2010.
- J. Lee, J. H. Mo, K. Katakura et al., “Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells,” Nature Cell Biology, vol. 8, no. 12, pp. 1327–1336, 2006.
- B. Slütter and W. Jiskoot, “Dual role of CpG as immune modulator and physical crosslinker in ovalbumin loaded N-trimethyl chitosan (TMC) nanoparticles for nasal vaccination,” Journal of Controlled Release, vol. 148, no. 1, pp. 117–121, 2010.
- J. L. Round, S. M. Lee, J. Li et al., “The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota,” Science, vol. 332, no. 6032, pp. 974–977, 2011.
- J. M. Otte, E. Cario, and D. K. Podolsky, “Mechanisms of Cross Hyporesponsiveness to Toll-Like Receptor Bacterial Ligands in Intestinal Epithelial Cells,” Gastroenterology, vol. 126, no. 4, pp. 1054–1070, 2004.
- V. Cerovic, C. D. Jenkins, A. G. C. Barnes, S. W. F. Milling, G. G. MacPherson, and L. S. Klavinskis, “Hyporesponsiveness of intestinal dendritic cells to TLR stimulation is limited to TLR4,” Journal of Immunology, vol. 182, no. 4, pp. 2405–2415, 2009.
- R. Zhou, H. Wei, R. Sun, J. Zhang, and Z. Tian, “NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 18, pp. 7512–7515, 2007.
- T. Karrasch, J. S. Kim, M. Muhlbauer, S. T. Magness, and C. Jobin, “Gnotobiotic IL-10-/-;NF-κBEGFP mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis,” Journal of Immunology, vol. 178, no. 10, pp. 6522–6532, 2007.
- M. Lotz, D. Gütle, S. Walther, S. Ménard, C. Bogdan, and M. W. Hornef, “Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells,” Journal of Experimental Medicine, vol. 203, no. 4, pp. 973–984, 2006.
- C. Chassin, M. Kocur, J. Pott et al., “MiR-146a mediates protective innate immune tolerance in the neonate intestine,” Cell Host and Microbe, vol. 8, no. 4, pp. 358–368, 2010.
- J. Wang, H. R. Ford, and A. V. Grishin, “NF-κB-mediated expression of MAPK phosphatase-1 is an early step in desensitization to TLR ligands in enterocytes,” Mucosal Immunology, vol. 3, no. 5, pp. 523–534, 2010.
- J. M. Wells, L. M. P. Loonen, and J. M. Karczewski, “The role of innate signaling in the homeostasis of tolerance and immunity in the intestine,” International Journal of Medical Microbiology, vol. 300, no. 1, pp. 41–48, 2010.
- S. L. Lebeis, B. Bommarius, C. A. Parkos, M. A. Sherman, and D. Kalman, “TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium,” Journal of Immunology, vol. 179, no. 1, pp. 566–577, 2007.
- K. Brandl, G. Plitas, B. Schnabl, R. P. DeMatteo, and E. G. Pamer, “MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection,” Journal of Experimental Medicine, vol. 204, no. 8, pp. 1891–1900, 2007.
- S. Rakoff-Nahoum, J. Paglino, F. Eslami-Varzaneh, S. Edberg, and R. Medzhitov, “Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis,” Cell, vol. 118, no. 2, pp. 229–241, 2004.
- S. Milling, U. Yrlid, V. Cerovic, and G. MacPherson, “Subsets of migrating intestinal dendritic cells,” Immunological Reviews, vol. 234, no. 1, pp. 259–267, 2010.
- B. M. Matta, A. Castellaneta, and A. W. Thomson, “Tolerogenic plasmacytoid DC,” European Journal of Immunology, vol. 40, no. 10, pp. 2667–2676, 2010.
- A. Goubier, B. Dubois, H. Gheit et al., “Plasmacytoid dendritic cells mediate oral tolerance,” Immunity, vol. 29, no. 3, pp. 464–475, 2008.
- U. Yrlid, S. W.F. Milling, J. L. Miller, S. Cartland, C. D. Jenkins, and G. G. MacPherson, “Regulation of intestinal dendritic cell migration and activation by plasmacytoid dendritic cells, TNF-α and type 1 IFNs after feeding a TLR7/8 ligand,” Journal of Immunology, vol. 176, no. 9, pp. 5205–5212, 2006.
- M. Miettinen, V. Veckman, S. Latvala, T. Sareneva, S. Matikainen, and I. Julkunen, “Live Lactobacillus rhamnosus and Streptococcus pyogenes differentially regulate Toll-like receptor (TLR) gene expression in human primary macrophages,” Journal of Leukocyte Biology, vol. 84, no. 4, pp. 1092–1100, 2008.
- C. Gómez-Llorente, S. Muñoz, and A. Gil, “Role of Toll-like receptors in the development of immunotolerance mediated by probiotics,” Proceedings of the Nutrition Society, vol. 69, no. 3, pp. 381–389, 2010.
- J. L. Coombes and F. Powrie, “Dendritic cells in intestinal immune regulation,” Nature Reviews Immunology, vol. 8, no. 6, pp. 435–446, 2008.
- T. Feng, A. T. Cao, C. T. Weaver, C. O. Elson, and Y. Cong, “Interleukin-12 converts Foxp3+ regulatory T cells to interferonγ-producing Foxp3+ T cells that inhibit colitis,” Gastroenterology, vol. 140, no. 7, pp. 2031–2043, 2011.
- J. L. Harden, T. Gu, M. O. Kilinc, R. B. Rowswell-Turner, L. P. Virtuoso, and N. K. Egilmez, “Dichotomous effects of IFN-γ on dendritic cell function determine the extent of IL-12 - driven antitumor T cell immunity,” Journal of Immunology, vol. 187, no. 1, pp. 126–132, 2011.
- A. Snchezfueyo and T. B. Strom, “Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs,” Gastroenterology, vol. 140, no. 1, pp. 51–64, 2011.
- G. Orlando, P. Hematti, R. J. Stratta et al., “Clinical operational tolerance after renal transplantation: current status and future challenges,” Annals of Surgery, vol. 252, no. 6, pp. 915–928, 2010.
- V. Sordi and L. Piemonti, “Therapeutic plasticity of stem cells and allograft tolerance,” Cytotherapy, vol. 13, no. 6, pp. 647–660, 2011.