Mediators of Inflammation

Mediators of Inflammation / 2010 / Article
Special Issue

Modulation of Toll-like Receptor Signalling as a New Therapeutic Principle

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Review Article | Open Access

Volume 2010 |Article ID 536478 |

Louise E. Pilsbury, Rachel L. Allen, Martin Vordermeier, "Modulation of Toll-Like Receptor Activity by Leukocyte Ig-Like Receptors and Their Effects during Bacterial Infection", Mediators of Inflammation, vol. 2010, Article ID 536478, 9 pages, 2010.

Modulation of Toll-Like Receptor Activity by Leukocyte Ig-Like Receptors and Their Effects during Bacterial Infection

Academic Editor: Philipp Lepper
Received23 Feb 2010
Accepted30 Mar 2010
Published20 Jun 2010


Toll-like receptors (TLRs) are a potent trigger for inflammatory immune responses. Without tight regulation their activation could lead to pathology, so it is imperative to extend our understanding of the regulatory mechanisms that govern TLR expression and function. One family of immunoregulatory proteins which can provide a balancing effect on TLR activity are the Leukocyte Ig-like receptors (LILRs), which act as innate immune receptors for self-proteins. Here we describe the LILR family, their inhibitory effect on TLR activity in cells of the monocytic lineage, their signalling pathway, and their antimicrobial effects during bacterial infection. Agents have already been identified which enhances or inhibits LILR activity raising the future possibility that modulation of LILR function could be used as a means to modulate TLR activity.

1. Toll-Like Receptor Activity and Antigen Presenting Cell Phenotype

Toll-like receptors (TLRs) are pattern recognition receptors with the ability to detect microbial products. They can provide the initial danger signal required to alert the body to bacterial or viral infection, playing a pivotal role in the activation of both innate and adaptive immune responses. TLRs recognise pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), a membrane component of gram negative bacteria; lipoproteins, functional proteins anchored to the cell membrane; flagellin, a major component of flagellum; heat shock proteins which are highly expressed during cellular stress and microbial nucleic acids [1, 2]. Ligation of individual or complex TLRs can activate different signalling pathways. Most TLRs signal via MyD88 resulting in NF- B or MAPK activation (Figure 1), ultimately leading to the transcription of genes associated with antimicrobial defence such as inflammatory cytokines, costimulation molecules, MHC, and nitric oxide (NO) [3, 4].

TLRs are widely expressed on immune cells and possess distinctive functions dependent on cell type and signalling pathway [5, 15]. We will focus on their effects on dendritic cells and macrophages, which can act as professional antigen presenting cells (APCs). The expression profile of TLRs on APCs varies between subsets (Table 1), which include plasmacytoid DCs (pDCs), myeloid DCs (mDCs), monocyte-derived DCs (moDCs), and macrophages. TLR signalling in these immune cell subsets triggers an activation programme that includes cytokine secretion; pDCs secrete type I interferons (IFN-α) which have a fundamental antiviral function through the recruitment of immune cells and their role in T cell differentiation [16]. In contrast, mDCs and moDCs primarily secrete IL-12, a potent proinflammatory cytokine involved in T cell differentiation and NK cell activation [17]. Macrophages, which provide an initial antimicrobial response, also secrete IL-12, NO, and TNF-α which play an important role in apoptotic cell death and bacterial lysis [18]. In addition to the production of soluble cytokines and chemokines, upregulation of various cell surface markers such as the costimulation molecules and MHC required for antigen presentation is also observed following TLR activity [19, 20]. Of these, the best defined costimulation molecules are CD80, CD86, and B7-H1. Both CD80 and CD86 bind to CD28 on T cells to provide an activating signal, whereas B7-H1 binds to PD1 to generate an inhibitory signal [21]. The type of costimulation molecules upregulated and cytokine profile secreted by an APC is thought to be determined by the activation signal given by individual TLRs, and can determine the nature of the downstream immune response [20, 22, 23].



Upon migration to the lymph nodes, activated DCs present microbial antigens to prime a specific T cell response. MHC class II-restricted antigens are recognised by T helper (Th) cells, which then secrete proinflammatory cytokines to recruit effector cells and aid in B cell maturation. Th cell responses are defined by their cytokine secretion profile. For example, the cytokines IL-12 and IFN-I dominate Th1 responses, resulting in the recruitment of proinflammatory effector cells and the clearance of infection. Th17 cells are also proinflammatory and through the secretion of IL-17 and IL-22 stimulate, for example, the secretion of antimicrobial proteins from other effector cells. For Th2 responses the cytokines IL-4 and IL-25 dominate, resulting in inhibition of proinflammatory cytokine secretion and further proliferation. Th1 responses are required for pathogen clearance. However, during excessive immune activation, Th1 responses may damage host tissues, raising the possibility of pathology or chronic inflammatory diseases. In order to prevent this, populations of Th2 and regulatory T cells (Tregs) are required, the effects of which regulate the Th1 response [24].

T cell polarisation to either Th1, Th2, or Th17 profile is dependent on the type of costimulation molecules and cytokines expressed by the APC [28, 29], which is in turn determined by TLR signalling profile. In this respect, signalling through individual or different combinations of TLR may control the nature of the adaptive immune response towards any given antigen [30]. TLR4, TLR7, and TLR8 are typically thought to trigger definitive Th1 responses, whereas TLR2 has been implicated in inducing Th2 responses. However, recent studies have demonstrated that simultaneous coligation of TLR2 with other TLRs alters the signalling profile and ultimately the DC signature required for T cell polarisation, and may dampen down TLR4 mediated responses [31]. Coligation with accessory molecules such as dectin-1 is also thought to play a part in polarising immune responses [32], and Eisenbarth et al. have demonstrated that levels of antigen stimulation may impact on DC signatures, with high levels of LPS triggering a Th1 response, and low levels a Th2 response [31, 33, 34].

As an invading pathogen is likely to possess multiple PAMPs and trigger several TLRs, any infection would be predicted to elicit multifaceted T cell responses. Furthermore, as TLRs are known to complex with other receptors and recruit adapter molecules involved in signalling cascades, it is possible that some of these interactions function as regulatory mechanisms. The mechanisms involved in TLR regulation are only just becoming clear. Scavenger receptor A (SRA or CD205) [39], and single Ig IL-1R-related molecule (SIGIRR)/Toll IL-1R8 have been described as candidate regulatory proteins [40]. Members of the leukocyte Ig-like receptor family (LILR, also known as ILTs, LIR, CD85, and MIR [4143]) have also become a focus for investigation after being shown to exert a powerful inhibitory effect on TLR functions [44] (Figure 2).

2. LILR and Their Murine Equivalents (PIR and LILRB4)

LILRs are a family of innate immune receptors that are predominantly expressed on antigen-presenting cells and B cells. The eleven members of the human LILRs family are split into three distinct groups: activating, inhibitory and soluble. The LILR classed as inhibitory (LILRB1-5) have a cytoplasmic tail containing 2–4 immunoreceptor tyrosine-based inhibitory domains (ITIMs). LILRs classed as activating (LILRA1-2, 4–6) lack any signalling motif, but instead possess a charged arginine residue which enables association with the adaptor protein FcεRIγ [45]. To date, this is the only identified adaptor molecule shown to associate with LILR, although it is possible that other adapter molecules are capable of this association. Signalling is then directed through the FcεRI -associated immnuoreceptors tyrosine-based activatory domains (ITAMs). Despite this classification, the so-called activating group contains receptors with the ability to exert inhibitory effects, a phenomenon that has been observed for several ITAM-bearing immune receptors and is thought to be related to strength of signalling [46].

LILRs are conserved throughout evolution and to date homologues have been identified in rodents [47], chickens [48], and cattle [49]. In rodents, LILR equivalents are known as paired immunoglobulin-like receptors, a family that contains multiple activating receptors (PIR-A) but only one inhibitory receptor, PIR-B [47, 5052]. PIRs were classified as LILR homologues due to their similarities in genetic sequence and location, expression profile, structure, and function [5355]. They have since proved to be an effective tool to examine the role of these receptors [51]. A further murine homologue, LILRB4 was previously known as gp49B [56].

Similar to TLRs, LILR expression varies between APC subsets (Table 1). MDC and moDCs express LILRA2, LILRB1, LILRB3, and LILRB4, whereas pDCs express LILRA4, LILRB1, and LILRB4 [6, 57]. LILRB1, LILRB4 and LILRA4 expression is decreased upon DC maturation [6, 58]. Individual receptors exert their regulatory function in a variety of ways. Upregulation and/or cross-linking of LILRB2 inhibits the upregulation of co-stimulatory molecules on APCs, resulting in T cell anergy [59]. In contrast, signalling through LILRA2 inhibits the upregulation of CD1b, HLA-DR, CD40, CD80, CD86 and, CD206, and prevents effective T cell activation and proliferation [60]. Unlike LILRB2, which inhibits APC effector functions by downregulating costimulation molecules, LILRB4 has recently been shown to inhibit APC response to bacterial infection by upregulating IL-10 production and subsequently downregulating IL-8 secretion. Ligation of LILRB4 does not appear to affect the expression of costimulation molecules [61]. However, Lu et al., demonstrated that LILRB4 was able to inhibit TNF-α release via inhibition of FcγRI signalling [62], in line with the ability of murine LILRB4 to inhibit inflammatory cytokine production [63]. LILRB4 has also been shown to be highly expressed in patients with malignancy, and this receptor is thought to play a critical role in the induction of tolerance. However, it is not known whether LILRB4 expression on malignant cells is induced by regulatory T cells, or if the LILRB4 expression binds to a T cell ligand rendering them anergic [63].

3. LILR Ligand Specificity and Signalling

Members of the LILR and PIR families have been shown to be involved in bacterial engagement [64]. Both PIR-A1 and PIR-B, and their corresponding human homologues LILRB1 and LILRB3 have been shown to bind bacteria including E. coli, H. pylori, and S. aureus [64]. The bacterial ligand(s) involved in this interaction are yet to be determined and individual receptors vary in their bacterial specificity. However, the most thoroughly characterised ligand for LILR is MHC class I (MHC-I). Unlike other MHC-I-specific receptors, LILRs show a broad specificity for classical and nonclassical forms of MHC-I; LILRB1 and LILRB2 bind all classical MHC-I as well as some nonclassical alleles [65]. LILRB2 has been shown to bind CD1d, which is an MHC-I-like molecule able to present nonprotein antigens to T cells [66]. CD1d is usually recognised by the TCR receptor of NKT cells, which results in the activation of proinflammatory effector cells and target cell lysis. LILR modulation of CD1d activity may therefore be of particular importance in bacterial infections, which can result in an overaccumulation of lipids in the infected cell [66, 67].

Inhibitory LILRs have been shown to exhibit their functions both independently and in association with activating receptors such as TLRs. Inhibitory LILR carry their own signalling motifs, varying from 2 to 4 ITIMs in their cytoplasmic tail. Variation in the number of ITIM domains has been proposed to result in signal amplification or the recruitment of alternative signalling molecules [7]. Upon activation phosphorylated tyrosines within an ITIM become docking sites for either the Src homology 2 domain-containing phosphatase 1 (SHP-1) or SHP-2, or the SH2 domain-containing inositol phosphatise (SHIP) [58]. These phosphatases then dephosphorylate key molecules further downstream in the cascade or those involved in the ITAM signalling of activating receptors, with consequent inhibitory effects [7]. SHP-2 is particularly important in both positive and negative regulation of cellular differentiation [58]. Although yet to be fully defined, these signalling patterns are likely to be found mimicked in the modulation of TLR activation [68, 69].

As mentioned previously, activating LILR has a positively charged arginine residue within the cytoplasmic domain, which enables association with adapter proteins, such as FcεRI When activated, tyrosine molecules in the ITAM domain of FcεRIγ are phosphorylated by protein tyrosine kinases of the Src family kinases, creating binding sites for further signalling molecules, such as zap70 or syc [7]. The recruited signalling molecules may differ depending on cell type, and therefore LILRs may be involved in modulating a wide range of intracellular signalling pathways [70].

3.1. LILR-Mediated Control of TLR Functions

LILR-mediated control of TLR activity has been documented for several different bacterial infections. In the case of S. aureus, LILR and PIR-B receptors can bind the pathogen in conjunction with TLR2 and trigger the release of inhibitory cytokines such as IL-10 [64]. Inhibition of TLR2 signalling by PIR-B was confirmed in a study of PIR- mice, where an excessive Th2 response was observed, coupled with impaired DC maturation. This inhibition of DC maturation was thought to arise from the absence of PIR-B regulation of a common signalling pathway used by IL-3, IL-5, and GM-CSF [71].

Evidence of a role for LILR (and their murine homologues) providing a counterbalance to TLR activity is most strikingly illustrated by the high mortality rate of Salmonella infection for mice lacking the inhibitory receptor PIR-B [72, 73]. Interestingly, instead of the exacerbated immune responses that might have been expected in the absence of an inhibitory receptor, PIR-B-deficient mice were actually more susceptible to Salmonella infection, caused by a decrease in phagosomal oxidant production, necessary for bacterial lysis within lysosomes [72].

Mycobacterium leprae infection can result in tuberculoid (T-lep) or lepromatous leprosy (L-lep). Patients with T-lep typically display a localised form of disease, with effective bacterial clearance. In L-lep, patients suffer from disseminated disease, with large numbers of bacilli. Although the factors that influence disease course are currently unknown, polymorphisms in TLR2/1 are thought to play a role [60]. In a study by Bleharski et al., gene expression analysis identified an up to 5.4-fold overexpression of LILRA2 in skin lesions of L-lep, compared to T-lep [73]. Infected macrophages stimulated with LILRA2 ligands showed a 40% reduction in antimicrobial responses, indicating that LILRA2 also inhibits antimicrobial functions in macrophages [73]. Furthermore, ligation of LILRA2 considerably reduced IL-12 production by TLRs, skewing cytokine activity towards a Th2-biased response. This is important as the immune response in T-lep lesions (where infection is generally contained then cleared) is Th1-biased, whereas L-lep with its higher bacterial loads and disseminated infection is Th2-biased. Therefore, it is possible that the overexpression of LILRA2 in L-lep results in an inadequate Th2-biased immune response and a more severe form of disease [60]. LILRB5, LILRB3, and LILRA3 are also overexpressed in L-lep patient lesions, although their relevance in infection has yet to be determined [70].

Signalling through different TLRs has been shown to result in different LILR expression profiles [6, 61, 74]. In human cells the inhibitory receptors LILRB2 and LILRB4 were upregulated following Salmonella infection, an effect which appears to be mediated largely by LPS recognition, as activation of LILRB4 also occurred by both heat-inactivated Salmonella and Salmonella LPS [61]. In this respect, LILRB4 may play an important role in TLR4 regulation. Similar relationships exist for other LILR and TLR: LILRA4 has been shown to regulate TLR7/9 activity in pDC and LILRA2 has been shown to inhibit TLR4-mediated activity.

In viral infections, the pDC subset plays an important role in mediating antiviral immunity upon activation by pathogenic ligands. TLR7/9, together with TLR3 and TLR8 are localised in endosomal/lysosomal compartments [75], where their activation leads to the production of TNF- and IFN-I, a group of potent antiviral cytokines. The newly-characterised receptor LILRA4 is expressed only on pDCs, where it appears to play an important role in the control of their activity in response to viral TLR stimulation. Following recognition of its ligand, tetherin (also known as BST2), LILRA4 downregulates TLR7 and TLR9-mediated production of IFN- and TNF- and decreases calcium mobilisation [76]. However, LILRA4 activity does not affect the maturation of the cell, as upregulation of CD80/CD86 is still observed. LILRA4 is also able to inhibit TLR7 and TLR9 signalling after prior antigen stimulation, but is selectively downregulated upon pDC activation [76, 77]. Similarly in murine models, PIR-B has been shown to inhibit TLR9-mediated signalling via Brutons tyrosine kinase (Btk) phosphorylation, which subsequently inhibits NF- B activation [78].

4. Modifying TLR Activity through LILR Signalling

Given the potent effects of LILR on TLR activity, there is the potential in future to use these receptors as a tool for therapeutic modulation of TLR signalling. For example, inhibitory LILR could be triggered by their highest affinity self-ligand, HLA-G [70]. This nonclassical MHC-I allele has a restricted distribution of expression, limited to placental trophoblast cells and thymus epithelial cells, but is overexpressed in certain pathologies including nonrejected allografts, HIV infection, and tumours [79, 80]. HLA-G expression is known to trigger the upregulation of LILR [80]. HLA-G also has a natural tendency to form disulphide-bonded dimers which in turn enhance binding to LILRB1 and LILRB2, resulting in enhanced immunosuppressive effects [81]. Thus, there is therapeutic potential for recombinant HLA-G to be used to downregulate TLR effects through enhancing LILR activity.

Enhancing LILR expression would be expected to exert a further dampening effect on TLR activity. Expression levels of LILR can also be enhanced by certain agents; Vitamin D3, Dexamethasone, and niflumic acid have been shown to up-regulate the expression of LILRB2 and LILRB4 on DCs, which is seen with an accompanying increase in IL-10 secretion and Treg differentiation. Although the exact mechanisms involved in tolerance induction in these studies are yet to be fully elucidated, high expression of LILRB4 is thought to be strongly associated with inhibition of NF- B activation [82, 83]. Recently a study examining the effects of 1,25(OH)2D3 on DCs demonstrated that this agent is able to up-regulate LILRB4 on moDCs and mDCs but not pDCs. This may be due to the fact that the normal expression levels of LILRB4 are markedly higher on pDCs than mDCs [84]. Further to this, the IDO activity in tryptophan (trp) deficient cells was used in a study recently to define mechanisms of DC tolerance and induction of Tregs. Brenk et al. found that upon DC tolerisation, high levels of LILRB3 and LILRB4 were upregulated. However, replacement of trp was unable to reverse the tolerogenic conditions, and DCs continued to stimulate T cells to differentiate into a regulatory phenotype. Furthermore, only by using anti-LILRB4 antibodies were they able to restore any function to the DCs and subsequently the T cells. The authors predict that DC regulation induced in this manner may affect the epigentics of foxP3 gene transcription and provide antigen-specific Treg cells, therefore providing a mechanism open to therapeutic manipulation [85].

Given the powerful inhibitory nature of LILR, it may be possible to modulate the expression of these receptors prior to or in conjunction with chemotherapies in order to enhance treatment efficacy. Blocking the inhibitory functions of LILR has been demonstrated recently in a study by Morel and Bellón, in which amoxicillin was shown to have the ability to interfere with LILRB1 recognition of MHC class I on NK cells, a finding which could potentially have a large impact on tumour immunology and therapeutics [86]. With further research, the bacterial interaction with LILR will most likely prove fundamental in defining regulatory pathways involved in TLR pathogen responses. As more ligands are discovered for these inhibitory receptors, the potential for development of novel therapies targeting specific LILR allows the possibility of shaping immune responses in disease settings.


  1. 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. View at: Google Scholar
  2. K. Takeda, T. Kaisho, and S. Akira, “Toll-like receptors,” Annual Review of Immunology, vol. 21, pp. 335–376, 2003. View at: Publisher Site | Google Scholar
  3. S. Akira, K. Takeda, and T. Kaisho, “Toll-like receptors: critical proteins linking innate and acquired immunity,” Nature Immunology, vol. 2, no. 8, pp. 675–680, 2001. View at: Publisher Site | Google Scholar
  4. S. Thoma-Uszynski, S. Stenger, O. Takeuchi et al., “Induction of direct antimicrobial activity through mammalian toll-like receptors,” Science, vol. 291, no. 5508, pp. 1544–1547, 2001. View at: Publisher Site | Google Scholar
  5. M. Muzio, N. Polentarutti, D. Bosisio, M. K. P. Prahladan, and A. Mantovani, “Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes,” Journal of Leukocyte Biology, vol. 67, no. 4, pp. 450–456, 2000. View at: Google Scholar
  6. X. S. Ju, C. Hacker, B. Scherer et al., “Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation,” Gene, vol. 331, no. 1-2, pp. 159–164, 2004. View at: Publisher Site | Google Scholar
  7. L. Borges and D. Cosman, “LIRs/ILTs/MIRs, inhibitory and stimulatory Ig-superfamily receptors expressed in myeloid and lymphoid cells,” Cytokine and Growth Factor Reviews, vol. 11, no. 3, pp. 209–217, 2000. View at: Publisher Site | Google Scholar
  8. A. C. I. Boullart, E. H. J. G. Aarntzen, P. Verdijk et al., “Maturation of monocyte-derived dendritic cells with Toll-like receptor 3 and 7/8 ligands combined with prostaglandin E results in high interleukin-12 production and cell migration,” Cancer Immunology, Immunotherapy, vol. 57, no. 11, pp. 1589–1597, 2008. View at: Publisher Site | Google Scholar
  9. A. Visintin, A. Mazzoni, J. H. Spitzer, D. H. Wyllie, S. K. Dower, and D. M. Segal, “Regulation of Toll-like receptors in human monocytes and dendritic cells,” Journal of Immunology, vol. 166, no. 1, pp. 249–255, 2001. View at: Google Scholar
  10. 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. View at: Google Scholar
  11. D. Belkin, M. Torkar, C. Chang et al., “Killer cell Ig-like receptor and leukocyte Ig-like receptor transgenic mice exhibit tissue- and cell-specific transgene expression,” Journal of Immunology, vol. 171, no. 6, pp. 3056–3063, 2003. View at: Google Scholar
  12. M. Cho, K. Ishida, J. Chen et al., “SAGE library screening reveals ILT7 as a specific plasmacytoid dendritic cell marker that regulates type I IFN production,” International Immunology, vol. 20, no. 1, pp. 155–164, 2008. View at: Publisher Site | Google Scholar
  13. L. Borges, M. Kubin, and T. Kuhlman, “LIR9, an immunoglobulin-superfamily-activating receptor, is expressed as a transmembrane and as a secreted molecule,” Blood, vol. 101, no. 4, pp. 1484–1486, 2003. View at: Publisher Site | Google Scholar
  14. D. C. Jones, A. Roghanian, D. P. Brown et al., “Alternative mRNA splicing creates transcripts encoding soluble proteins from most LILR genes,” European Journal of Immunology, vol. 39, no. 11, pp. 3195–3206, 2009. View at: Publisher Site | Google Scholar
  15. 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. View at: Google Scholar
  16. A. G. Jegalian, F. Facchetti, and E. S. Jaffe, “Plasmacytoid dendritic cells physiologic roles and pathologic states,” Advances in Anatomic Pathology, vol. 16, no. 6, pp. 392–404, 2009. View at: Publisher Site | Google Scholar
  17. M. J. Brunda, “Interleukin-12,” Journal of Leukocyte Biology, vol. 55, no. 2, pp. 280–288, 1994. View at: Google Scholar
  18. D. M. Mosser, “The many faces of macrophage activation,” Journal of Leukocyte Biology, vol. 73, no. 2, pp. 209–212, 2003. View at: Publisher Site | Google Scholar
  19. K. S. Michelsen, A. Aicher, M. Mohaupt et al., “The role of toll-like receptors (TLRs) in bacteria-induced maturation of murine dendritic cells (DCs): peptidoglycan and lipoteichoic acid are inducers of DC maturation and require TLR2,” Journal of Biological Chemistry, vol. 276, no. 28, pp. 25680–25686, 2001. View at: Publisher Site | Google Scholar
  20. F. Re and J. L. Strominger, “Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells,” Journal of Biological Chemistry, vol. 276, no. 40, pp. 37692–37699, 2001. View at: Publisher Site | Google Scholar
  21. L. Chen, “Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity,” Nature Reviews Immunology, vol. 4, no. 5, pp. 336–347, 2004. View at: Google Scholar
  22. M. U. Martin and H. Wesche, “Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family,” Biochimica et Biophysica Acta, vol. 1592, no. 3, pp. 265–280, 2002. View at: Publisher Site | Google Scholar
  23. T. Horng, G. M. Barton, R. A. Flavell, and R. Medzhitov, “The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors,” Nature, vol. 420, no. 6913, pp. 329–333, 2002. View at: Publisher Site | Google Scholar
  24. K. Dabbagh and D. B. Lewis, “Toll-like receptors and T-helper-1/T-helper-2 responses,” Current Opinion in Infectious Diseases, vol. 16, no. 3, pp. 199–204, 2003. View at: Google Scholar
  25. G. C. Sen and S. N. Sarkar, “Transcriptional signaling by double-stranded RNA: role of TLR3,” Cytokine and Growth Factor Reviews, vol. 16, no. 1, pp. 1–14, 2005. View at: Publisher Site | Google Scholar
  26. E. Meylan and J. Tschopp, “IRAK2 takes its place in TLR signaling,” Nature Immunology, vol. 9, no. 6, pp. 581–582, 2008. View at: Publisher Site | Google Scholar
  27. B. Malissen and J. J. Ewbank, “‘TaiLoRing’ the response of dendritic cells to pathogens,” Nature Immunology, vol. 6, no. 8, pp. 749–750, 2005. View at: Publisher Site | Google Scholar
  28. V. Ubaldi, L. Gatta, L. Pace, G. Doria, and C. Pioli, “CTLA-4 engagement inhibits Th2 but not Th1 cell polarisation,” Clinical and Developmental Immunology, vol. 10, no. 1, pp. 13–17, 2003. View at: Publisher Site | Google Scholar
  29. S. D. Reid, G. Penna, and L. Adorini, “The control of T cell responses by dendritic cell subsets,” Current Opinion in Immunology, vol. 12, no. 1, pp. 114–121, 2000. View at: Publisher Site | Google Scholar
  30. K. Ozato, H. Tsujimura, and T. Tamura, “Toll-like receptor signaling and regulation of cytokine gene expression in the immune system,” BioTechniques, vol. 33, no. 4, pp. S66–S75, 2002. View at: Google Scholar
  31. M. H. Wenink, K. C. Santegoets, J. C. 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. View at: Google Scholar
  32. D. M. Underhill, “Collaboration between the innate immune receptors dectin-1, TLRs, and Nods,” Immunological Reviews, vol. 219, no. 1, pp. 75–87, 2007. View at: Publisher Site | Google Scholar
  33. 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. View at: Publisher Site | Google Scholar
  34. E. van Riet, B. Everts, K. Retra et al., “Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlates for Th1/Th2 polarization,” BMC Immunology, vol. 10, article 9, 2009. View at: Publisher Site | Google Scholar
  35. L. A. J. O'Neill, “‘Fine tuning’ TLR signaling,” Nature Immunology, vol. 9, no. 5, pp. 459–461, 2008. View at: Publisher Site | Google Scholar
  36. T. Lang and A. Mansell, “The negative regulation of Toll-like receptor and associated pathways,” Immunology and Cell Biology, vol. 85, no. 6, pp. 425–434, 2007. View at: Publisher Site | Google Scholar
  37. J. M. Cavaillon and M. Adib-Conquy, “Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis,” Critical Care, vol. 10, no. 5, article 233, 2006. View at: Publisher Site | Google Scholar
  38. S. M. Dauphinee and A. Karsan, “Lipopolysaccharide signaling in endothelial cells,” Laboratory Investigation, vol. 86, no. 1, pp. 9–22, 2006. View at: Publisher Site | Google Scholar
  39. H. Yi, X. Yu, P. Gao et al., “Pattern recognition scavenger receptor SRA/CD204 down-regulates Toll-like receptor 4 signaling-dependent CD8 T-cell activation,” Blood, vol. 113, no. 23, pp. 5819–5828, 2009. View at: Publisher Site | Google Scholar
  40. K. Bulek, S. Swaidani, J. Qin et al., “The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of Th2 immune response,” Journal of Immunology, vol. 182, no. 5, pp. 2601–2609, 2009. View at: Publisher Site | Google Scholar
  41. J. Samaridis and M. Colonna, “Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways,” European Journal of Immunology, vol. 27, no. 3, pp. 660–665, 1997. View at: Publisher Site | Google Scholar
  42. M. Cella, C. Döhring, J. Samaridis et al., “A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing,” Journal of Experimental Medicine, vol. 185, no. 10, pp. 1743–1752, 1997. View at: Publisher Site | Google Scholar
  43. D. Cosman, N. Fanger, L. Borges et al., “A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules,” Immunity, vol. 7, no. 2, pp. 273–282, 1997. View at: Publisher Site | Google Scholar
  44. K. J. Anderson and R. L. Allen, “Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells,” Immunology, vol. 127, no. 1, pp. 8–17, 2009. View at: Publisher Site | Google Scholar
  45. H. Nakajima, J. Samaridis, L. Angman, and M. Colonna, “Cutting edge: human myeloid cells express an activating ILT receptor (ILT1) that associates with Fc receptor γ-chain,” Journal of Immunology, vol. 162, no. 1, pp. 5–8, 1999. View at: Google Scholar
  46. A. David and J. Trowsdale, “You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling,” European Journal of Immunology, vol. 36, no. 7, pp. 1646–1653, 2006. View at: Publisher Site | Google Scholar
  47. K. Hayami, D. Fukuta, Y. Nishikawa et al., “Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors,” Journal of Biological Chemistry, vol. 272, no. 11, pp. 7320–7327, 1997. View at: Publisher Site | Google Scholar
  48. B. C. Viertlboeck, F. A. Habermann, R. Schmitt, M. A. M. Groenen, L. D. Pasquier, and T. W. Göbel, “The chicken leukocyte receptor complex: a highly diverse multigene family encoding at least six structurally distinct receptor types,” Journal of Immunology, vol. 175, no. 1, pp. 385–393, 2005. View at: Google Scholar
  49. C. G. Elsik, R. L. Tellam, K. C. Worley et al., “The genome sequence of taurine cattle: a window to ruminant biology and evolution,” Science, vol. 324, no. 5926, pp. 522–528, 2009. View at: Publisher Site | Google Scholar
  50. H. Kubagawa, P. D. Burrows, and M. D. Cooper, “A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5261–5266, 1997. View at: Publisher Site | Google Scholar
  51. T. Takai and M. Ono, “Activating and inhibitory nature of the murine paired immunoglobulin-like receptor family,” Immunological Reviews, vol. 181, pp. 215–222, 2001. View at: Publisher Site | Google Scholar
  52. T. Tun, Y. Kubagawa, G. Dennis, P. D. Burrows, M. D. Cooper, and H. Kubagawa, “Genomic structure of mouse PIR-A6, an activating member of the paired immunoglobulin-like receptor gene family,” Tissue Antigens, vol. 61, no. 3, pp. 220–230, 2003. View at: Publisher Site | Google Scholar
  53. T. Takai, “Paired immunoglobulin-like receptors and their MHC class I recognition,” Immunology, vol. 115, no. 4, pp. 433–440, 2005. View at: Publisher Site | Google Scholar
  54. Y. Yamashita, M. Ono, and T. Takai, “Inhibitory and stimulatory functions of paired Ig-like receptor (PIR) family in RBL-2H3 cells,” Journal of Immunology, vol. 161, no. 8, pp. 4042–4047, 1998. View at: Google Scholar
  55. Y. Yamashita, D. Fukuta, A. Tsuji et al., “Genomic structures and chromosomal location of p91, a novel murine regulatory receptor family,” Journal of Biochemistry, vol. 123, no. 2, pp. 358–368, 1998. View at: Google Scholar
  56. S. Kasai, M. Inui, K. Nakamura et al., “A novel regulatory role of gp49B on dendritic cells in T-cell priming,” European Journal of Immunology, vol. 38, no. 9, pp. 2426–2437, 2008. View at: Publisher Site | Google Scholar
  57. M. Cella, D. Jarrossay, F. Faccheth et al., “Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon,” Nature Medicine, vol. 5, no. 8, pp. 919–923, 1999. View at: Publisher Site | Google Scholar
  58. A. Verbrugge, T. De Ruiter, C. Geest, P. J. Coffer, and L. Meyaard, “Differential expression of leukocyte-associated Ig-like receptor-1 during neutrophil differentiation and activation,” Journal of Leukocyte Biology, vol. 79, no. 4, pp. 828–836, 2006. View at: Publisher Site | Google Scholar
  59. M. B. Feinberg and G. Silvestri, “T cells and immune tolerance induction: a regulatory renaissance?” Nature Immunology, vol. 3, no. 3, pp. 215–217, 2002. View at: Publisher Site | Google Scholar
  60. D. J. Lee, P. A. Sieling, M. T. Ochoa et al., “LILRA2 activation inhibits dendritic cell differentiation and antigen presentation to T cells,” Journal of Immunology, vol. 179, no. 12, pp. 8128–8136, 2007. View at: Google Scholar
  61. D. P. Brown, D. C. Jones, K. J. Anderson et al., “The inhibitory receptor LILRB4 (ILT3) modulates antigen presenting cell phenotype and, along with LILRB2 (ILT4), is upregulated in response to Salmonella infection,” BMC Immunology, vol. 10, article 56, 2009. View at: Publisher Site | Google Scholar
  62. H. K. Lu, C. Rentero, M. J. Raftery, L. Borges, K. Bryant, and N. Tedla, “Leukocyte Ig-like receptor B4 (LILRB4) is a potent inhibitor of FcγRI-mediated monocyte activation via dephosphorylation of multiple kinases,” Journal of Biological Chemistry, vol. 284, no. 50, pp. 34839–34848, 2009. View at: Publisher Site | Google Scholar
  63. G. Vlad, C.-C. Chang, A. I. Colovai, P. Berloco, R. Cortesini, and N. Suciu-Foca, “Immunoglobulin-like transcript 3: a crucial regulator of dendritic cell function,” Human Immunology, vol. 70, no. 5, pp. 340–344, 2009. View at: Publisher Site | Google Scholar
  64. M. Nakayama, D. M. Underhill, T. W. Petersen et al., “Paired Ig-like receptors bind to bacteria and shape TLR-mediated cytokine production,” Journal of Immunology, vol. 178, no. 7, pp. 4250–4259, 2007. View at: Google Scholar
  65. P. Parham, “Immunogenetics of killer-cell immunoglobulin-like receptors,” Tissue Antigens, vol. 62, no. 3, pp. 194–200, 2003. View at: Publisher Site | Google Scholar
  66. C. S. C. Chui and D. Li, “Role of immunolglobulin-like transcript family receptors and their ligands in suppressor T-cell-induced dendritic cell tolerization,” Human Immunology, vol. 70, no. 9, pp. 686–691, 2009. View at: Publisher Site | Google Scholar
  67. J. Wang, Y. Li, Y. Kinjo et al., “Lipid binding orientation within CD1d affects recognition of Borrelia burgorferi antigens by NKT cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 4, pp. 1535–1540, 2010. View at: Publisher Site | Google Scholar
  68. K. Hirayasu, J. Ohashi, H. Tanaka et al., “Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians,” American Journal of Human Genetics, vol. 82, no. 5, pp. 1075–1083, 2008. View at: Publisher Site | Google Scholar
  69. O. A. Huynh, T. Hampartzoumian, J. P. Arm et al., “Down-regulation of leucocyte immunoglobulin-like receptor expression in the synovium of rheumatoid arthritis patients after treatment with disease-modifying anti-rheumatic drugs,” Rheumatology, vol. 46, no. 5, pp. 742–751, 2007. View at: Publisher Site | Google Scholar
  70. D. Brown, J. Trowsdale, and R. Allen, “The LILR family: modulators of innate and adaptive immune pathways in health and disease,” Tissue Antigens, vol. 64, no. 3, pp. 215–225, 2004. View at: Publisher Site | Google Scholar
  71. A. Ujike, K. Takeda, A. Nakamura, S. Ebihara, K. Akiyama, and T. Takai, “Impaired dendritic cell maturation and increased TH2 responses in PIR-B/ mice,” Nature Immunology, vol. 3, no. 6, pp. 542–548, 2002. View at: Publisher Site | Google Scholar
  72. I. Torii, S. Oka, M. Hotomi et al., “PIR-B-deficient mice are susceptible to Salmonella infection,” Journal of Immunology, vol. 181, no. 6, pp. 4229–4239, 2008. View at: Google Scholar
  73. J. R. Bleharski, H. Li, C. Meinken et al., “Use of genetic profiling in leprosy to discriminate clinical forms of the disease,” Science, vol. 301, no. 5639, pp. 1527–1530, 2003. View at: Publisher Site | Google Scholar
  74. N. Cohen, J. Morisset, and D. Emilie, “Induction of tolerance by Porphyromonas gingivalis on APCs: a mechanism implicated in periodontal infection,” Journal of Dental Research, vol. 83, no. 5, pp. 429–433, 2004. View at: Google Scholar
  75. T. Nishiya and A. L. DeFranco, “Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors,” Journal of Biological Chemistry, vol. 279, no. 18, pp. 19008–19017, 2004. View at: Publisher Site | Google Scholar
  76. 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. View at: Publisher Site | Google Scholar
  77. W. Cao, L. Bover, M. Cho et al., “Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction,” Journal of Experimental Medicine, vol. 206, no. 7, pp. 1603–1614, 2009. View at: Publisher Site | Google Scholar
  78. T. Kubo, Y. Uchida, Y. Watanabe et al., “Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity,” Journal of Experimental Medicine, vol. 206, no. 9, pp. 1971–1982, 2009. View at: Publisher Site | Google Scholar
  79. M. Shiroishi, K. Tsumoto, K. Amano et al., “Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 15, pp. 8856–8861, 2003. View at: Publisher Site | Google Scholar
  80. J. LeMaoult, K. Zafaranloo, C. Le Banff, and E. D. Carosella, “HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells,” FASEB Journal, vol. 19, no. 6, pp. 662–664, 2005. View at: Publisher Site | Google Scholar
  81. R. Apps, L. Gardner, A. M. Sharkey, N. Holmes, and A. Moffett, “A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1,” European Journal of Immunology, vol. 37, no. 7, pp. 1924–1937, 2007. View at: Publisher Site | Google Scholar
  82. A. E. Pedersen, M. Gad, M. R. Walter, and M. H. Claesson, “Induction of regulatory dendritic cells by dexamethasone and 1α,25-dihydroxyvitamin D,” Immunology Letters, vol. 91, no. 1, pp. 63–69, 2004. View at: Publisher Site | Google Scholar
  83. U. Švajger, A. Vidmar, and M. Jeras, “Niflumic acid renders dendritic cells tolerogenic and up-regulates inhibitory molecules ILT3 and ILT4,” International Immunopharmacology, vol. 8, no. 7, pp. 997–1005, 2008. View at: Publisher Site | Google Scholar
  84. L. Adorini, N. Giarratana, and G. Penna, “Pharmacological induction of tolerogenic dendritic cells and regulatory T cells,” Seminars in Immunology, vol. 16, no. 2, pp. 127–134, 2004. View at: Publisher Site | Google Scholar
  85. M. Brenk, M. Scheler, S. Koch et al., “Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+Foxp3+ T regulatory cells,” Journal of Immunology, vol. 183, no. 1, pp. 145–154, 2009. View at: Publisher Site | Google Scholar
  86. E. Morel and T. Bellón, “Amoxicillin conjugates to HLA class I molecules and interferes with signalling through the ILT2/LIR-1/CD85j inhibitory receptor,” Allergy, vol. 62, no. 2, pp. 190–196, 2007. View at: Publisher Site | Google Scholar

Copyright © 2010 Louise E. Pilsbury 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.

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