Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2008 (2008), Article ID 106321, 10 pages
http://dx.doi.org/10.1155/2008/106321
Review Article

Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity

1Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA
2Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA

Received 20 August 2008; Accepted 12 October 2008

Academic Editor: Michel Goldman

Copyright © 2008 Jorge Schettini and Pinku Mukherjee. 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.

Abstract

Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients.

1. Introduction

There is not a clear answer why tumor immunity is not effectively mounted in most tumor-bearing hosts. Early mouse studies, as well as clinical experience, indicate that the immune system can recognize and reject tumors [111]. On the contrary, immune-deficient mice and patients have an augmented incidence of cancer which suggests a relevant role for the immune system [12, 13]. Immunotherapeutic protocols based on these findings have been developed; however, the results are variable and limited [1419]. As observed in melanoma and other tumors, there is an absence of specific cytotoxic T lymphocytes (CTLs) expansion in cancer patients. This suggests that tumor-antigens may not overcome the threshold on the surface of DCs needed to trigger CTL proliferation (passive factor). In addition, immunoregulatory factors are involved in downregulating T cell proliferation and inducing T regulatory cells (active factors), secreted by tumor cells [14]. Thus, DCs play a critical role in inducing and regulating the immune responses [20, 21].

DCs constitute a heterogeneous cell population, which are classified according to cluster of differentiation (CD) expression, functionality, and localization, playing a pivotal role in the control of innate and adaptive immune responses [22]. Generally, DCs’ life cycle is based on a model commonly referred to as the “Langerhans cells paradigm” [23]. Immature DCs are strategically located in peripheral and interstitial spaces of most tissues, and from their location, and always in surveillance mode, DCs constitutively take up antigens from the environment, which will be associated with the MHC molecules. Coordinately, DCs mature by cessation of phagocytosis and endocytosis and move toward the draining lymphoid nodes (LNs) due to upregulation of chemokine receptor CCR7, thereby, acquiring responsiveness to a chemotactic gradient of CCL21(-Leu/-Ser) and CCL19 expressed by initial and terminal lymphatic vessels and by mature DCs, respectively [24, 25].

After arriving at the draining lymphoid nodes, DCs are able to present antigens in the context of MHC and costimulatory molecules to antigen-specific T cells. This induces a cellular immune response which drives T cells to differentiate to effectors cells [26, 27]. Moreover, DCs are important in starting adaptive and innate immunity, by activating naïve and memory B cells, natural killer, and natural killer T cells [2831].

Due to the antigen capturing and presenting properties of DCs, ex vivo delivery of tumor-antigen to DCs has been used as a strategy to guarantee successful antigen presentation to T cells [14]. However, the efficacy of this approach to therapeutic vaccination has been limited in both preclinical and clinical settings [19, 32]. This suggests that we need to better understand and refine the parameters to establish the optimal conditions for vaccination against cancer.

Recent progress in the identification of distinct DC subsets has been done. Analysis of the DC population in several lymphoid organs has shown a considerable heterogeneity, where some subsets of DCs follow the “Langerhans cell paradigm”, but not all of them [33, 34]. Unfortunately, the heterogeneity of the human DC network is poorly understood compared with the mouse DC network. At present, there are two main pathways of differentiation in mouse DCs. The myeloid pathway generates two subsets: Langerhans cells and interstitial DCs, whereas the lymphoid pathway generates plasmacytoid DCs (pDCs) [22, 28, 35]. In contrast to the many studies in mouse DCs, there are very few studies on mature human DCs from tissue. Human blood DCs are heterogeneous in their expression of markers, but this may reflect differences in the activation or maturation states of DCs rather than separate lineages [36]. However, from in vitro studies, it is possible to deduce pathways of human dendritic cell development. Similar to mouse DCs, the myeloid pathway in humans generates Langerhans cells and interstitial DCs. Blood monocytes, named precursors DC1 (pDC1), are the most commonly used precursor cells for generating human DCs in culture. In the presence of GM-CSF and IL-4, pDC1 can generate DCs called DC1. Maturation of these cells is achieved by stimulating cytokines or microbial products [22, 3739]. The human lymphoid pathway also generates pDCs, termed pDC2. These cells are type I IFN producing cells (IPCs) and they were discovered before their mouse counterparts. The pDC2 responds to viral and microbial stimuli by producing type I IFNs [35]. Both human and mouse pDCs can be maturated with bacterial stimuli or viruses. Upon maturation, human pDC2, named DC2, lacks typical myeloid markers, such as its precursor, but displays the characteristic of mature DCs [40, 41].

Although most studies have focused on the role of pDCs in antiviral immunity, several new lines of evidence have suggested that pDCs are also involved in tumor immunity, as well as in promoting peripheral tolerance [4247]. Interestingly, pDCs can synthesize large amount of functional indoleamine 2,3-dioxygenase (IDO), which requires autocrine release of type I IFN, upon Toll-like receptor-9 (TLR9) and CD200R ligands stimulation. IDO secretion by pDCs promotes T-cell death at T-cell areas of secondary lymphoid organs. Notably, through the upregulation of inducible T-cell costimulator ligand (ICOSL), pDCs have the ability to generate regulatory T cells [48, 49]. Gathering together, this evidence suggests that pDCs represent a key effector cell in both innate and adaptive immunity regulation [35, 5053]. In this review, we focus on the characterization, physiology, and potential roles of pDCs in the antitumor responses.

2. Differentiation and Trafficking Patterns of pDCs

The growth factor fms-like tyrosine kinase 3 ligand (FLT3-L) has been described as a key differentiation and trafficking factor for human and mouse pDCs from hematopoietic progenitor cells (HPCs). FLT3-L injection in humans causes an increase of both myeloid DCs (mDCs) and pDCs in the blood. In mice, FLT3-L injection induces the generation of mDCs and pDCs in blood, lymphoid tissues, liver, and lung [5459]. In vitro, mDC and pDCs can be generated from FLT3-L-supplemented BM culture system [60, 61]. Recently, Fancke et al. have also shown that M-CSF is capable of driving pDCs from bone marrow precursor cells in vitro and in vivo [62].

pDCs account for less than 1% of total peripheral blood mononuclear cells (PBMCs) and can be isolated through removal of lineage-positive cells and (IL-3R). The identification of two markers on human (BDCA-2 and BDCA-4) and one in the mouse (PDCA-1) has facilitated the isolation of pDCs from PBMC or lymphoid organs by positive selection with magnetic beads coupled with specific monoclonal antibodies [63, 64].

In human and mice, pDCs have been found circulating in the blood and cord blood of neonates [6567]. Interestingly, human pDCs have been found in fetal liver, thymus, and bone marrow suggesting that pDCs develop from human stem cells (HSCs) within these primary lymphoid tissues [68]. Moreover, pDCs can be located in lymphoid nodes, spleen, tonsils, and Peyer’s patches.

Similar to B and T cell migration patterns, pDCs leave the bone marrow and migrate into the T cell rich areas of the secondary lymphoid tissues, through high-endothelial venules (HEVs) in the lymph nodes, mucosa-associated lymphoid tissues, and through marginal zones of the spleen under steady-state conditions [6973]. This unique migration pattern of pDCs among DCs appears to be connected with their expression of CD62L and CCR7, which allows the pDCs ligate L-selectin ligands expressed by HEV and chemokines CCL19 and CCL21 expressed by HEVs and stromal cells within the T-cell rich areas, respectively [73, 74].

The expressions of chemokine receptors on circulating blood mDCs and pDCs are similar. However, the level of CCR5, CCR7, and CXCR3 expressions is clearly divergent in these two subsets, being higher on pDCs than on mDCs [74]. Among these two subsets, pDCs are also the only to migrate in response to the homeostatic chemokine SDF-1/CXCL12, the ligand of CXCR4, which is expressed on dermal endothelial cells, in HEVs of lymphoid nodes, and in malignant cells [44]. This evidence suggests that pDCs may reach lymph nodes using CXCR4, and also explains their fundamental localization in the secondary lymphoid organs [70].

Interestingly, human pDCs have been found to infiltrate primary and malignant melanoma, head and neck carcinoma, ovarian carcinoma, and breast cancer [4246, 75], as well as cutaneous inflammatory lesions, which may be dependent on their ability to express CLA, which binds to E-selectin on dermal endothelial cells and may enhance their recruitment to the inflammatory site [76].

3. Activation of Plasmacytoid DCs

Virtually, all cell types are able to produce type I IFNs in response to viral exposure. The amount, kinetics, and types of IFN will depend on the cell type. However, pDCs are considered the professional type I IFN producing cells [35]. pDCs can produce 100–1000 times more type I IFN than the other blood cell types upon activation [35], or the equivalent of 10 pg/cell [77]. Myeloid DCs can also secrete type I IFN in response to RNA viruses, but less efficiently than pDCs [78].

It is important to note that not all viruses can activate pDCs to produce IFNs. Also, pDCs do not require to be infected to secrete type I IFN [79, 80]. Once secreted, type I IFNs induce MxA, an IFNα-inducible intracellular protein [75], oligoadenylate synthetase, and double-stranded RNA-(dsRNA-)-dependent protein kinase (PKR). Together, these proteins have the biological role in inducing cellular resistance by blocking viral replication, and, therefore, viral spread [81].

Moreover, type I IFN modulates several aspects of the immune response, including pDC survival, mDCs differentiation [82], modulation of Th1 and T-cell responses, cross-presentation and cross-priming independent of T helper cells [83], upregulation of MHC and costimulatory molecules, activation of NK cells, and induction of primary antibody responses [84].

pDC activation with pathogens or oligodeoxynucleotides (ODNs) with multiple unmethylated CpG dinucleotides induces the secretion of several other cytokines and chemokines, such as TNFα, IL-1, and IL-6. In mouse, but not in humans, pDCs have the capacity to synthesize bioactive IL-12, although this capacity still remains controversial [8587]. Virally, stimulated pDC produces chemokines, such as CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CXCL8 (IL-8), and CXCL10 (IP-10) which stimulate Th1, and NK cells homing to site of infection through IP-10 and CCL4, respectively [88, 89].

4. Regulation of Type I IFN Synthesis on pDCs

This unique subset of DCs can secrete type I IFNs faster than other cells to a wider range of viral and nonviral stimuli. Moreover, pDCs express a broader profile of IFNA genes than other antigen-presenting cells (APCs). In humans, the type I IFN family consists of 13 IFNα subtypes, one IFNβ, one IFN-ω, one IFN-κ, and one IFN-τ. IFNα1 is the major subtype expressed by pDCs, but other subtypes are also secreted, including IFNα2, -α5, -α8, -α10, and -α14 and a recently described family of IFNλ1-3 (also named IL-29, IL-28A, and IL-28B, resp.) [90, 91].

What makes pDCs synthesize type I IFN faster than other cells? Recently, it has been shown that transcription factors of the family of interferon regulatory factors (IRFs) play an important role in the regulation of interferon gene transcription. Nine mammalian IRF family members have been identified to guide the induction of IFN production, as well as to regulate and differentiate various cells types [92]. Expression of IRF-3 supports induction of IFNβ and IRF-5 or IRF-7 is sufficient to stimulate IFNα genes expression. Unlike other cells, pDCs have been shown to express constitutively higher levels of IRF-5, -7, and -8 mRNA, which might explain why this particular subset of DCs secrete faster and large quantities of type I IFNs than other cell types [93, 94].

5. Differential Expression and Function of TLRs in pDCs

This unique ability of pDCs to secrete large amounts of type I IFN depends on cellular receptors able to sense several types of nucleic acid. TLR is a family of 11 pattern recognition receptors (PRRs) which mediate the recognition of many pathogens through the detection of distinct pathogen-associated molecular patterns (PAMPs) [95, 96].

pDCs and mDCs each has a different TLR expression profile. In humans, mDCs can express TLR-1, -2, -3, -4, -5, -7, and -8, while pDCs express mainly TLR7 and -9 [97, 98]. Uniquely, TLR-7, -8, and -9 detect PAMPs in endosomal/lysosomal compartments followed by acidification [99, 100]. Transcriptional regulation of IFNβ and IFNα genes on pDCs is controlled mainly by IRF-3 and IRF-5/7. IRF-3 can be activated by TLR-3 and TLR-4, but there is no evidence of this pathway on pDCs. Instead, IRF-7 has a constitutively high expression in pDCs and it is recruited by myeloid differentiation primary response gene 88 (MyD88) through the adaptor molecule TRAF6 when TLR-7 or -9 is triggered [101].

Many studies have shown that exposure to synthetic TLR-7 or -9 agonists (e.g., imidazoquinoline, CpG ODN) induces pDCs to secrete IFNα and proinflammatory cytokines (IL-8 and TNFα), maturation, which heighten their T-cell stimulatory capacity [97, 102104].

Interestingly, endogenous antigens, such as DNA from necrotic cells, may be taken up by pDCs and signal through TLR-9 in autoimmune diseases [105]. TLR-9 agonist has a therapeutic potential and it has been used to induce innate and adaptive immune responses. Synthetic TLR-9 agonists are currently being tested in multiple phase II and phase III human clinical trial as adjuvants to cancer vaccine and in combination with conventional chemotherapy and others protocols [106108].

6. pDCs Can Link Innate and Adaptive Immunity via Type I IFNs

There are abundant studies in human and mice showing the importance of type I IFN to regulate inflammation and link innate and adaptive immunity [113115]. IFNα and -β are considered as important components of innate immunity together with their well-known antiviral activity [114]. Type I IFN released by human pDCs activates NK cell cytolytic activity, and also induces IFNγ production in NK cells through IL-12 secretion [116, 117]. Although with different molecular mechanisms in human and mice, type I IFN secreted by pDCs, upon stimulation, can affect T-cell functions. Thus, activated pDCs can induce T cells to make IL-10 and IFNγ [113, 118], and also induce a Th1 polarization [119]. It has also been reported that type I IFN can induce early activation markers (CD69) on T cells, long-term survival [120], and generation of a long-term antitumor immune response [121]. Recently, several studies have provided important evidence for a role of type I IFN in the differentiation of the Th1 subset [122], in the generation and activity of CTLs, as well as in supporting in vivo proliferation and survival of T cells [123, 124]. Altogether, these studies have led to the recognition of an important role of this cytokine in linking innate with adaptive immunity [115, 125].

On the other hand, murine pDCs can also inhibit certain mDCs functions. Upon infection, mice pDCs are the primary source of IFNα and IL-12, and type I IFNs they produce inhibit the synthesis of IL-12 from mDCs, a critical immunostimulatory cytokine of the T-cell-mediated immunity [79]. In human, the production of IL-12 by pDCs is still controversial, but some studies claimed the contrary [98, 126].

Interestingly, pDCs are critical for the generation of plasma cells and antibody responses. It appears that the depletion of pDCs from human blood abrogates the secretion of IgGs in response to viral infection. Furthermore, activated pDCs can induce activated B cells to differentiate plasma cells. Through Type I IFN and IL-6 secreted by pDCs, B cells are induced to develop into plasmablast and differentiate into antibody-secreting plasma cells [29].

7. Plasmacytoid DCs and Their Role in Cancer Immunity

Before the maturation of pDCs, they have a poor T-cell stimulation capacity. Early experiments reported that CD40L in combination with IL-3-stimulated pDCs develop into a functionally distinct DCs type that promotes the development of IL-4-secreting Th2 cells [40]. Also, pDCs can prime Th1 or Th0 allogeneic responses [118, 127, 128]. Furthermore, pDCs mature following exposure to influenza virus and exhibited an equivalent efficiency to expand the repertoire of anti-influenza virus cytotoxic T lymphocytes and Th1 T cells [104, 129].

It is clear now that immature mDCs and pDCs infiltrate solid tumor and lack the ability to induce T-cell activation [75]. However, they still present tumor antigens and induce IL-10-producing / regulatory T cells that inhibit antitumor immunity [130]. Nevertheless, using an anti-IL-10 mAb and CpG ODN, it is possible to induce a robust antitumor CTL response and tumor rejection in vivo [111]. Recently, murine pDCs have been described to have the ability to elicit in vivo, in naïve mice, an antigen-specific T cell response against endogenous antigens, as well as exogenous peptides, but not against exogenous antigens, and were capable of protecting mice from tumor challenge [131].

It has also been reported that human tumor antigens pulsed pDCs in vitro can prime IFNγ-secreting melanoma-specific CTLs [42]. Synergy among DC subsets has not been fully explored in the development of antitumor immunity. An interesting study has shown that immunizations with a mixture of matured pDCs plus mDCs resulted in increased levels of antigen-specific T cells and an enhanced antitumor response compared with immunization with either dendritic cell subset alone [109]. Altogether, these studies suggest that it is possible to re-establish and/or maximize an antitumor immune response when pDCs are taken in the regimen [132137] (Table 1).

tab1
Table 1

8. Clinical Significance of pDCs

There is evidence that pDCs are located in several types of tumors: head and neck cancer, ovarian cancer, primary melanoma cancer, and breast cancer [4246, 75]. Secreted factors by tumor cells may inhibit pDCs function, such as TGFβ, vascular endothelial growth factor β (VEGFβ), and IL-10.

On the contrary, other studies have reported that pDCs and tumor-infiltrating DC (TIDC) are functional and fully competent APCs. Isolation of TIDC showed an intermediate maturation phenotype and the capacity to take up particles, as well as produce IL-12 and maintain its migratory capacity. Infiltrating pDCs are capable of producing IFNα, as well as inducing complete regression or significant reduction of melanomas after a topically treatment of imiquimod (a small synthetic immune response modifier recognized by TLR7) [46, 110, 138, 139]. In addition, intratumoral stimulation of pDCs with TLR7 and -9 agonists has been successfully used in the clinic to treat basal cell carcinoma, human papillomavirus-infected warts, and condylomata accuminata [140, 141]. TLR signaling on pDCs can be used to induce type I IFNs and possibly protect DCs from tumor-derived inhibitory factors (such as VEGFβ or IL-10), as well as support T-cell survival, therefore, improving vaccination efficacy [112, 142147].

Thus, it will be critical to evaluate if stimulation of pDCs may overcome tumor-mediated inhibitory effects and can enhance a local antitumor immunity.

9. Conclusions

DCs are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDCs as a main source of type I IFN is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with others therapies.

A rational manipulation and design of vaccines which could include DCs subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients.

Acknowledgments

The authors would like to thank Teresa Tinder for helpful review of this manuscript. This work was funded by Pancreas SPORE Grant (P50 CA102701).

References

  1. K. Inaba, J. P. Metlay, M. T. Crowley, and R. M. Steinman, “Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ,” The Journal of Experimental Medicine, vol. 172, no. 2, pp. 631–640, 1990. View at Publisher · View at Google Scholar
  2. T. Sornasse, V. Flamand, G. de Becker et al., “Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo,” The Journal of Experimental Medicine, vol. 175, no. 1, pp. 15–21, 1992. View at Publisher · View at Google Scholar
  3. L. Zitvogel, J. I. Mayordomo, T. Tjandrawan et al., “Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines,” The Journal of Experimental Medicine, vol. 183, no. 1, pp. 87–97, 1996. View at Publisher · View at Google Scholar
  4. C. M. Celluzzi, J. I. Mayordomo, W. J. Storkus, M. T. Lotze, and L. D. Falo Jr., “Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity,” The Journal of Experimental Medicine, vol. 183, no. 1, pp. 283–287, 1996. View at Publisher · View at Google Scholar
  5. S. K. Nair, D. Snyder, B. T. Rouse, and E. Gilboa, “Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts,” International Journal of Cancer, vol. 70, no. 6, pp. 706–715, 1997. View at Publisher · View at Google Scholar
  6. F. Fu, Y. Li, S. Qian et al., “Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80(dim), CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients,” Transplantation, vol. 62, no. 5, pp. 659–665, 1996. View at Publisher · View at Google Scholar
  7. J. Ma, W. J. Urba, L. Si, Y. Wang, B. A. Fox, and H.-M. Hu, “Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution,” European Journal of Immunology, vol. 33, no. 8, pp. 2123–2132, 2003. View at Publisher · View at Google Scholar
  8. W. Asavaroengchai, Y. Kotera, and J. J. Mulé, “Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 2, pp. 931–936, 2002. View at Publisher · View at Google Scholar
  9. T. Boon, J.-C. Cerottini, B. van den Eynde, P. van der Bruggen, and A. van Pel, “Tumor antigens recognized by T lymphocytes,” Annual Review of Immunology, vol. 12, no. 1, pp. 337–365, 1994. View at Publisher · View at Google Scholar
  10. P. van der Bruggen, C. Traversari, P. Chomez et al., “A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma,” Science, vol. 254, no. 5038, pp. 1643–1647, 1991. View at Publisher · View at Google Scholar
  11. S. A. Rosenberg, Y. Kawakami, P. F. Robbins, and R.-F. Wang, “Identification of the genes encoding cancer antigens: implications of cancer immunotherapy,” Advances in Cancer Research, vol. 70, pp. 145–177, 1996. View at Publisher · View at Google Scholar
  12. A. S. Dighe, E. Richards, L. J. Old, and R. D. Schreiber, “Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFNγ receptors,” Immunity, vol. 1, no. 6, pp. 447–456, 1994. View at Publisher · View at Google Scholar
  13. S. Euvrard, J. Kanitakis, and A. Claudy, “Skin cancers after organ transplantation,” The New England Journal of Medicine, vol. 348, no. 17, pp. 1681–1691, 2003. View at Publisher · View at Google Scholar
  14. I. D. Davis, M. Jefford, P. Parente, and J. Cebon, “Rational approaches to human cancer immunotherapy,” Journal of Leukocyte Biology, vol. 73, no. 1, pp. 3–29, 2003. View at Publisher · View at Google Scholar
  15. O. J. Finn, “Cancer vaccines: between the idea and the reality,” Nature Reviews Immunology, vol. 3, no. 8, pp. 630–641, 2003. View at Publisher · View at Google Scholar
  16. S. Antonia, J. J. Mulé, and J. S. Weber, “Current developments of immunotherapy in the clinic,” Current Opinion in Immunology, vol. 16, no. 2, pp. 130–136, 2004. View at Publisher · View at Google Scholar
  17. E. C. Hsueh and D. L. Morton, “Antigen-based immunotherapy of melanoma: canvaxin therapeutic polyvalent cancer vaccine,” Seminars in Cancer Biology, vol. 13, no. 6, pp. 401–407, 2003. View at Publisher · View at Google Scholar
  18. V. K. Sondak and J. A. Sosman, “Results of clinical trials with an allogeneic melanoma tumor cell lysate vaccine: melacine®,” Seminars in Cancer Biology, vol. 13, no. 6, pp. 409–415, 2003. View at Publisher · View at Google Scholar
  19. P. Mukherjee, C. S. Madsen, A. R. Ginardi et al., “Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer,” Journal of Immunotherapy, vol. 26, no. 1, pp. 47–62, 2003. View at Publisher · View at Google Scholar
  20. S. Yamazaki, T. Iyoda, K. Tarbell et al., “Direct expansion of functional CD25+CD4+ regulatory T cells by antigen-processing dendritic cells,” The Journal of Experimental Medicine, vol. 198, no. 2, pp. 235–247, 2003. View at Publisher · View at Google Scholar
  21. H. Jonuleit, E. Schmitt, G. Schuler, J. Knop, and A. H. Enk, “Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells,” The Journal of Experimental Medicine, vol. 192, no. 9, pp. 1213–1222, 2000. View at Publisher · View at Google Scholar
  22. K. Shortman and Y.-J. Liu, “Mouse and human dendritic cell subtypes,” Nature Reviews Immunology, vol. 2, no. 3, pp. 151–161, 2002. View at Publisher · View at Google Scholar
  23. R. M. Steinman, “The dendritic cell system and its role in immunogenicity,” Annual Review of Immunology, vol. 9, pp. 271–296, 1991. View at Publisher · View at Google Scholar
  24. I. Mellman and R. M. Steinman, “Dendritic cells: specialized and regulated antigen processing machines,” Cell, vol. 106, no. 3, pp. 255–258, 2001. View at Publisher · View at Google Scholar
  25. G. J. Randolph, V. Angeli, and M. A. Swartz, “Dendritic-cell trafficking to lymph nodes through lymphatic vessels,” Nature Reviews Immunology, vol. 5, no. 8, pp. 617–628, 2005. View at Publisher · View at Google Scholar
  26. E. Ingulli, A. Mondino, A. Khoruts, and M. K. Jenkins, “In vivo detection of dendritic cell antigen presentation to CD4+ T cells,” The Journal of Experimental Medicine, vol. 185, no. 12, pp. 2133–2141, 1997. View at Publisher · View at Google Scholar
  27. J. M. Austyn, “New insights into the mobilization and phagocytic activity of dendritic cells,” The Journal of Experimental Medicine, vol. 183, no. 4, pp. 1287–1292, 1996. View at Publisher · View at Google Scholar
  28. C. Caux, C. Massacrier, B. Vanbervliet et al., “CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor a: II. Functional analysis,” Blood, vol. 90, no. 4, pp. 1458–1470, 1997. View at Google Scholar
  29. G. Jego, A. K. Palucka, J.-P. Blanck, C. Chalouni, V. Pascual, and J. Banchereau, “Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6,” Immunity, vol. 19, no. 2, pp. 225–234, 2003. View at Publisher · View at Google Scholar
  30. N. C. Fernandez, A. Lozier, C. Flament et al., “Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo,” Nature Medicine, vol. 5, no. 4, pp. 405–411, 1999. View at Publisher · View at Google Scholar
  31. N. Kadowaki, S. Antonenko, S. Ho et al., “Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells,” The Journal of Experimental Medicine, vol. 193, no. 10, pp. 1221–1226, 2001. View at Publisher · View at Google Scholar
  32. S. A. Rosenberg, J. C. Yang, and N. P. Restifo, “Cancer immunotherapy: moving beyond current vaccines,” Nature Medicine, vol. 10, no. 9, pp. 909–915, 2004. View at Publisher · View at Google Scholar
  33. K. Shortman and S. H. Naik, “Steady-state and inflammatory dendritic-cell development,” Nature Reviews Immunology, vol. 7, no. 1, pp. 19–30, 2007. View at Publisher · View at Google Scholar
  34. J. A. Villadangos and W. R. Heath, “Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm,” Seminars in Immunology, vol. 17, no. 4, pp. 262–272, 2005. View at Publisher · View at Google Scholar
  35. Y.-J. Liu, “IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors,” Annual Review of Immunology, vol. 23, no. 1, pp. 275–306, 2005. View at Publisher · View at Google Scholar
  36. D. N. J. Hart, “Dendritic cells: unique leukocyte populations which control the primary immune response,” Blood, vol. 90, no. 9, pp. 3245–3287, 1997. View at Google Scholar
  37. A. Bender, M. Sapp, G. Schuler, R. M. Steinman, and N. Bhardwaj, “Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood,” Journal of Immunological Methods, vol. 196, no. 2, pp. 121–135, 1996. View at Publisher · View at Google Scholar
  38. F. Sallusto and A. Lanzavecchia, “Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α,” The Journal of Experimental Medicine, vol. 179, no. 4, pp. 1109–1118, 1994. View at Publisher · View at Google Scholar
  39. N. Romani, D. Reider, M. Heuer et al., “Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability,” Journal of Immunological Methods, vol. 196, no. 2, pp. 137–151, 1996. View at Publisher · View at Google Scholar
  40. M.-C. Rissoan, V. Soumelis, N. Kadowaki et al., “Reciprocal control of T helper cell and dendritic cell differentiation,” Science, vol. 283, no. 5405, pp. 1183–1186, 1999. View at Publisher · View at Google Scholar
  41. G. Grouard, M.-C. Rissoan, L. Filgueira, I. Durand, J. Banchereau, and Y.-J. Liu, “The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand,” The Journal of Experimental Medicine, vol. 185, no. 6, pp. 1101–1111, 1997. View at Publisher · View at Google Scholar
  42. M. Salio, M. Cella, W. Vermi et al., “Plasmacytoid dendritic cells prime IFN-?-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions,” European Journal of Immunology, vol. 33, no. 4, pp. 1052–1062, 2003. View at Publisher · View at Google Scholar
  43. E. Hartmann, B. Wollenberg, S. Rothenfusser et al., “Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer,” Cancer Research, vol. 63, no. 19, pp. 6478–6487, 2003. View at Google Scholar
  44. W. Zou, V. Machelon, A. Coulomb-L'Hermin et al., “Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells,” Nature Medicine, vol. 7, no. 12, pp. 1339–1346, 2001. View at Publisher · View at Google Scholar
  45. I. Treilleux, J.-Y. Blay, N. Bendriss-Vermare et al., “Dendritic cell infiltration and prognosis of early stage breast cancer,” Clinical Cancer Research, vol. 10, no. 22, pp. 7466–7474, 2004. View at Publisher · View at Google Scholar
  46. F. Palamara, S. Meindl, M. Holcmann, P. Lührs, G. Stingl, and M. Sibilia, “Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod,” The Journal of Immunology, vol. 173, no. 5, pp. 3051–3061, 2004. View at Google Scholar
  47. B. J. Weigel, N. Nath, P. A. Taylor et al., “Comparative analysis of murine marrow-derived dendritic cells generated by Flt3L or GM-CSF/IL-4 and matured with immune stimulatory agents on the in vivo induction of antileukemia responses,” Blood, vol. 100, no. 12, pp. 4169–4176, 2002. View at Publisher · View at Google Scholar
  48. A. E. Morelli and A. W. Thomson, “Tolerogenic dendritic cells and the quest for transplant tolerance,” Nature Reviews Immunology, vol. 7, no. 8, pp. 610–621, 2007. View at Publisher · View at Google Scholar
  49. F. Fallarino, C. Asselin-Paturel, C. Vacca et al., “Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement,” The Journal of Immunology, vol. 173, no. 6, pp. 3748–3754, 2004. View at Google Scholar
  50. M. Colonna, G. Trinchieri, and Y.-J. Liu, “Plasmacytoid dendritic cells in immunity,” Nature Immunology, vol. 5, no. 12, pp. 1219–1226, 2004. View at Publisher · View at Google Scholar
  51. S. M. M. Haeryfar, “The importance of being a pDC in antiviral immunity: the IFN mission versus Ag presentation?” Trends in Immunology, vol. 26, no. 6, pp. 311–317, 2005. View at Publisher · View at Google Scholar
  52. K. McKenna, A.-S. Beignon, and N. Bhardwaj, “Plasmacytoid dendritic cells: linking innate and adaptive immunity,” Journal of Virology, vol. 79, no. 1, pp. 17–27, 2005. View at Publisher · View at Google Scholar
  53. Y.-J. Liu, “Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity,” Cell, vol. 106, no. 3, pp. 259–262, 2001. View at Publisher · View at Google Scholar
  54. B. Pulendran, J. L. Smith, G. Caspary et al., “Distinct dendritic cell subsets differentially regulate the class of immune response in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 3, pp. 1036–1041, 1999. View at Publisher · View at Google Scholar
  55. E. Maraskovsky, K. Brasel, M. Teepe et al., “Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified,” The Journal of Experimental Medicine, vol. 184, no. 5, pp. 1953–1962, 1996. View at Publisher · View at Google Scholar
  56. B. Pulendran, J. Lingappa, M. K. Kennedy et al., “Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice,” The Journal of Immunology, vol. 159, no. 5, pp. 2222–2231, 1997. View at Google Scholar
  57. E. Maraskovsky, E. Daro, E. Roux et al., “In vivo generation of human dendritic cell subsets by Flt3 ligand,” Blood, vol. 96, no. 3, pp. 878–884, 2000. View at Google Scholar
  58. B. Pulendran, J. Banchereau, S. Burkeholder et al., “Flt3-ligand and granulocyte colony-stimulating factor mobilize distinct human dendritic cell subsets in vivo,” The Journal of Immunology, vol. 165, no. 1, pp. 566–572, 2000. View at Google Scholar
  59. M. R. Shurin, P. P. Pandharipande, T. D. Zorina et al., “FLT3 ligand induces the generation of functionally active dendritic cells in mice,” Cellular Immunology, vol. 179, no. 2, pp. 174–184, 1997. View at Publisher · View at Google Scholar
  60. K. Brasel, T. De Smedt, J. L. Smith, and C. R. Maliszewski, “Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures,” Blood, vol. 96, no. 9, pp. 3029–3039, 2000. View at Google Scholar
  61. M. Gilliet, A. Boonstra, C. Paturel et al., “The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor,” The Journal of Experimental Medicine, vol. 195, no. 7, pp. 953–958, 2002. View at Publisher · View at Google Scholar
  62. B. Fancke, M. Suter, H. Hochrein, and M. O'Keeffe, “M-CSF: a novel plasmacytoid and conventional dendritic cell poietin,” Blood, vol. 111, no. 1, pp. 150–159, 2008. View at Publisher · View at Google Scholar
  63. S. Blomberg, M.-L. Eloranta, M. Magnusson, G. V. Alm, and L. Rönnblom, “Expression of the markers BDCA-2 and BDCA-4 and production of interferon-α by plasmacytoid dendritic cells in systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 48, no. 9, pp. 2524–2532, 2003. View at Publisher · View at Google Scholar
  64. A. Krug, A. R. French, W. Barchet et al., “TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function,” Immunity, vol. 21, no. 1, pp. 107–119, 2004. View at Publisher · View at Google Scholar
  65. U. O'Doherty, M. Peng, S. Gezelter et al., “Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature,” Immunology, vol. 82, no. 3, pp. 487–493, 1994. View at Google Scholar
  66. R. V. Sorg, G. Kögler, and P. Wernet, “Identification of cord blood dendritic cells as an immature CD11c- population,” Blood, vol. 93, no. 7, pp. 2302–2307, 1999. View at Google Scholar
  67. Y. Kamogawa-Schifter, J. Ohkawa, S. Namiki, N. Arai, K.-I. Arai, and Y. Liu, “Ly49Q defines 2 pDC subsets in mice,” Blood, vol. 105, no. 7, pp. 2787–2792, 2005. View at Publisher · View at Google Scholar
  68. B. Blom, S. Ho, S. Antonenko, and Y.-J. Liu, “Generation of interferon α-producing predendritic cell (pre-DC)2 from human CD34+ hematopoietic stem cells,” The Journal of Experimental Medicine, vol. 192, no. 12, pp. 1785–1796, 2000. View at Publisher · View at Google Scholar
  69. M. Cella, D. Jarrossay, F. Facchetti 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 · View at Google Scholar
  70. G. Penna, M. Vulcano, S. Sozzani, and L. Adorini, “Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells,” Human Immunology, vol. 63, no. 12, pp. 1164–1171, 2002. View at Publisher · View at Google Scholar
  71. A. Blasius, W. Vermi, A. Krug, F. Facchetti, M. Cella, and M. Colonna, “A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha,” Blood, vol. 103, no. 11, pp. 4201–4206, 2004. View at Publisher · View at Google Scholar
  72. C. Asselin-Paturel, G. Brizard, J.-J. Pin, F. Brière, and G. Trinchieri, “Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody,” The Journal of Immunology, vol. 171, no. 12, pp. 6466–6477, 2003. View at Google Scholar
  73. H. Yoneyama, K. Matsuno, Y. Zhang et al., “Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules,” International Immunology, vol. 16, no. 7, pp. 915–928, 2004. View at Publisher · View at Google Scholar
  74. G. Penna, S. Sozzani, and L. Adorini, “Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells,” The Journal of Immunology, vol. 167, no. 4, pp. 1862–1866, 2001. View at Google Scholar
  75. W. Vermi, R. Bonecchi, F. Facchetti et al., “Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas,” The Journal of Pathology, vol. 200, no. 2, pp. 255–268, 2003. View at Publisher · View at Google Scholar
  76. C. Bangert, J. Friedl, G. Stary, G. Stingl, and T. Kopp, “Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease?” Journal of Investigative Dermatology, vol. 121, no. 6, pp. 1409–1418, 2003. View at Publisher · View at Google Scholar
  77. P. Fitzgerald-Bocarsly, M. Feldman, M. Mendelsohn, S. Curl, and C. Lopez, “Human mononuclear cells which produce interferon-alpha during NK(HSV-FS) assays are HLA-DR positive cells distinct from cytolytic natural killer effectors,” Journal of Leukocyte Biology, vol. 43, no. 4, pp. 323–334, 1988. View at Google Scholar
  78. M. Cella, M. Salio, Y. Sakakibara, H. Langen, I. Julkunen, and A. Lanzavecchia, “Maturation, activation, and protection of dendritic cells induced by double-stranded RNA,” The Journal of Experimental Medicine, vol. 189, no. 5, pp. 821–829, 1999. View at Publisher · View at Google Scholar
  79. M. Dalod, T. P. Salazar-Mather, L. Malmgaard et al., “Interferon a/ß and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo,” The Journal of Experimental Medicine, vol. 195, no. 4, pp. 517–528, 2002. View at Publisher · View at Google Scholar
  80. M. Dalod, T. Hamilton, R. Salomon et al., “Dendritic cell responses to early murine cytomegalovirus infection: subset functional specialization and differential regulation by interferon a/ß,” The Journal of Experimental Medicine, vol. 197, no. 7, pp. 885–898, 2003. View at Publisher · View at Google Scholar
  81. A. J. Sadler and B. R. G. Williams, “Interferon-inducible antiviral effectors,” Nature Reviews Immunology, vol. 8, no. 7, pp. 559–568, 2008. View at Publisher · View at Google Scholar
  82. M. Montoya, G. Schiavoni, F. Mattei et al., “Type I interferons produced by dendritic cells promote their phenotypic and functional activation,” Blood, vol. 99, no. 9, pp. 3263–3271, 2002. View at Publisher · View at Google Scholar
  83. A. Le Bon, N. Etchart, C. Rossmann et al., “Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon,” Nature Immunology, vol. 4, no. 10, pp. 1009–1015, 2003. View at Publisher · View at Google Scholar
  84. A. Le Bon, G. Schiavoni, G. D'Agostino, I. Gresser, F. Belardelli, and D. F. Tough, “Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo,” Immunity, vol. 14, no. 4, pp. 461–470, 2001. View at Publisher · View at Google Scholar
  85. O. Duramad, K. L. Fearon, J. H. Chan et al., “IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences,” Blood, vol. 102, no. 13, pp. 4487–4492, 2003. View at Publisher · View at Google Scholar
  86. A. Krug, S. Rothenfusser, V. Hornung et al., “Identification of CpG oligonucleotide sequences with high induction of IFN-a/ß in plasmacytoid dendritic cells,” European Journal of Immunology, vol. 31, no. 7, pp. 2154–2163, 2001. View at Publisher · View at Google Scholar
  87. M. Schnurr, T. Toy, A. Shin, G. Hartmann, S. Rothenfusser, and J. Soellner, “Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells,” Blood, vol. 103, no. 4, pp. 1391–1397, 2004. View at Publisher · View at Google Scholar
  88. N. J. Megjugorac, H. A. Young, S. B. Amrute, S. L. Olshalsky, and P. Fitzgerald-Bocarsly, “Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells,” Journal of Leukocyte Biology, vol. 75, no. 3, pp. 504–514, 2004. View at Publisher · View at Google Scholar
  89. B. Piqueras, J. Connolly, H. Freitas, A. K. Palucka, and J. Banchereau, “Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors,” Blood, vol. 107, no. 7, pp. 2613–2618, 2006. View at Publisher · View at Google Scholar
  90. S. V. Kotenko, G. Gallagher, V. V. Baurin et al., “IFN-?s mediate antiviral protection through a distinct class II cytokine receptor complex,” Nature Immunology, vol. 4, no. 1, pp. 69–77, 2003. View at Publisher · View at Google Scholar
  91. P. Sheppard, W. Kindsvogel, W. Xu et al., “IL-28, IL-29 and their class II cytokine receptor IL-28R,” Nature Immunology, vol. 4, no. 1, pp. 63–68, 2003. View at Publisher · View at Google Scholar
  92. K. Ozato, P. Tailor, and T. Kubota, “The interferon regulatory factor family in host defense: mechanism of action,” The Journal of Biological Chemistry, vol. 282, no. 28, pp. 20065–20069, 2007. View at Publisher · View at Google Scholar
  93. A. Izaguirre, B. J. Barnes, S. Amrute et al., “Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells,” Journal of Leukocyte Biology, vol. 74, no. 6, pp. 1125–1138, 2003. View at Publisher · View at Google Scholar
  94. P. Tailor, T. Tamura, and K. Ozato, “IRF family proteins and type I interferon induction in dendritic cells,” Cell Research, vol. 16, no. 2, pp. 134–140, 2006. View at Publisher · View at Google Scholar
  95. C. A. Janeway Jr. and R. Medzhitov, “Innate immune recognition,” Annual Review of Immunology, vol. 20, no. 1, pp. 197–216, 2002. View at Google Scholar
  96. K. Takeda, T. Kaisho, and S. Akira, “Toll-like receptors,” Annual Review of Immunology, vol. 21, pp. 335–376, 2003. View at Google Scholar
  97. H. Hemmi, T. Kaisho, O. Takeuchi et al., “Small-antiviral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway,” Nature Immunology, vol. 3, no. 2, pp. 196–200, 2002. View at Publisher · View at Google Scholar
  98. 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. View at Publisher · View at Google Scholar
  99. F. Heil, P. Ahmad-Nejad, H. Hemmi et al., “The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily,” European Journal of Immunology, vol. 33, no. 11, pp. 2987–2997, 2003. View at Publisher · View at Google Scholar
  100. E. Latz, A. Schoenemeyer, A. Visintin et al., “TLR9 signals after translocating from the ER to CpG DNA in the lysosome,” Nature Immunology, vol. 5, no. 2, pp. 190–198, 2004. View at Publisher · View at Google Scholar
  101. T. Kawai, S. Sato, K. J. Ishii et al., “Interferon-a induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6,” Nature Immunology, vol. 5, no. 10, pp. 1061–1068, 2004. View at Publisher · View at Google Scholar
  102. C. L. Ahonen, S. J. Gibson, R. M. Smith et al., “Dendritic cell maturation and subsequent enhanced T-cell stimulation induced with the novel synthetic immune response modifier R-848,” Cellular Immunology, vol. 197, no. 1, pp. 62–72, 1999. View at Publisher · View at Google Scholar
  103. T. Ito, R. Amakawa, T. Kaisho et al., “Interferon-a and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets,” The Journal of Experimental Medicine, vol. 195, no. 11, pp. 1507–1512, 2002. View at Publisher · View at Google Scholar
  104. K. Loré, M. R. Betts, J. M. Brenchley et al., “Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses,” The Journal of Immunology, vol. 171, no. 8, pp. 4320–4328, 2003. View at Google Scholar
  105. F. J. Barrat, T. Meeker, J. Gregorio et al., “Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus,” The Journal of Experimental Medicine, vol. 202, no. 8, pp. 1131–1139, 2005. View at Publisher · View at Google Scholar
  106. A. M. Krieg, “Therapeutic potential of Toll-like receptor 9 activation,” Nature Reviews Drug Discovery, vol. 5, no. 6, pp. 471–484, 2006. View at Publisher · View at Google Scholar
  107. A. M. Krieg, “Development of TLR9 agonists for cancer therapy,” The Journal of Clinical Investigation, vol. 117, no. 5, pp. 1184–1194, 2007. View at Publisher · View at Google Scholar
  108. Y. M. Murad, T. M. Clay, H. K. Lyerly, and M. A. Morse, “CPG-7909 (PF-3512676, ProMune®): Toll-like receptor-9 agonist in cancer therapy,” Expert Opinion on Biological Therapy, vol. 7, no. 8, pp. 1257–1266, 2007. View at Publisher · View at Google Scholar
  109. Y. Lou, C. Liu, G. J. Kim, Y.-J. Liu, P. Hwu, and G. Wang, “Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses,” The Journal of Immunology, vol. 178, no. 3, pp. 1534–1541, 2007. View at Google Scholar
  110. O. Preynat-Seauve, P. Schuler, E. Contassot, F. Beermann, B. Huard, and L. E. French, “Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection,” The Journal of Immunology, vol. 176, no. 1, pp. 61–67, 2006. View at Google Scholar
  111. A. P. Vicari, C. Chiodoni, C. Vaure et al., “Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody,” The Journal of Experimental Medicine, vol. 196, no. 4, pp. 541–549, 2002. View at Publisher · View at Google Scholar
  112. M. Pashenkov, G. Goëss, C. Wagner et al., “Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 24, no. 36, pp. 5716–5724, 2006. View at Google Scholar
  113. N. Kadowaki, S. Antonenko, J. Y.-N. Lau, and Y.-J. Liu, “Natural interferon α/β-producing cells link innate and adaptive immunity,” The Journal of Experimental Medicine, vol. 192, no. 2, pp. 219–226, 2000. View at Publisher · View at Google Scholar
  114. C. A. Biron, “Interferons α and β as immune regulators—a new look,” Immunity, vol. 14, no. 6, pp. 661–664, 2001. View at Publisher · View at Google Scholar
  115. K. Hoebe, E. Janssen, and B. Beutler, “The interface between innate and adaptive immunity,” Nature Immunology, vol. 5, no. 10, pp. 971–974, 2004. View at Publisher · View at Google Scholar
  116. G. Trinchieri, D. Santoli, R. R. Dee, and B. B. Knowles, “Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation,” The Journal of Experimental Medicine, vol. 147, no. 5, pp. 1299–1313, 1978. View at Publisher · View at Google Scholar
  117. S. Bandyopadhyay, B. Perussia, G. Trinchieri, D. S. Miller, and S. E. Starr, “Requirement for HLA-DR+ accessory cells in natural killing of cytomegalovirus-infected fibroblasts,” The Journal of Experimental Medicine, vol. 164, no. 1, pp. 180–195, 1986. View at Publisher · View at Google Scholar
  118. M. Cella, F. Facchetti, A. Lanzavecchia, and M. Colonna, “Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization,” Nature Immunology, vol. 1, no. 4, pp. 305–310, 2000. View at Publisher · View at Google Scholar
  119. A. Langenkamp, K. Nagata, K. Murphy, L. Wu, A. Lanzavecchia, and F. Sallusto, “Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells,” European Journal of Immunology, vol. 33, no. 2, pp. 474–482, 2003. View at Publisher · View at Google Scholar
  120. D. Agnello, C. S. R. Lankford, J. Bream et al., “Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights,” Journal of Clinical Immunology, vol. 23, no. 3, pp. 147–161, 2003. View at Publisher · View at Google Scholar
  121. F. Belardelli and I. Gresser, “The neglected role of type I interferon in the T-cell response: implications for its clinical use,” Immunology Today, vol. 17, no. 8, pp. 369–372, 1996. View at Google Scholar
  122. M. Mohty, A. Vialle-Castellano, J. A. Nunes, D. Isnardon, D. Olive, and B. Gaugler, “IFN-α skews monocyte differentiation into toll-like receptor 7-expressing dendritic cells with potent functional activities,” The Journal of Immunology, vol. 171, no. 7, pp. 3385–3393, 2003. View at Google Scholar
  123. F. Belardelli, M. Ferrantini, E. Proietti, and J. M. Kirkwood, “Interferon-alpha in tumor immunity and immunotherapy,” Cytokine & Growth Factor Reviews, vol. 13, no. 2, pp. 119–134, 2002. View at Publisher · View at Google Scholar
  124. M. Ferrantini and F. Belardelli, “Gene therapy of cancer with interferon: lessons from tumor models and perspectives for clinical applications,” Seminars in Cancer Biology, vol. 10, no. 2, pp. 145–157, 2000. View at Publisher · View at Google Scholar
  125. R. Baccala, K. Hoebe, D. H. Kono, B. Beutler, and A. N. Theofilopoulos, “TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity,” Nature Medicine, vol. 13, no. 5, pp. 543–551, 2007. View at Publisher · View at Google Scholar
  126. A. Dzionek, Y. Inagaki, K. Okawa et al., “Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions,” Human Immunology, vol. 63, no. 12, pp. 1133–1148, 2002. View at Publisher · View at Google Scholar
  127. T. Ito, R. Amakawa, M. Inaba et al., “Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and type I IFNs,” The Journal of Immunology, vol. 172, no. 7, pp. 4253–4259, 2004. View at Google Scholar
  128. J.-F. Fonteneau, M. Larsson, A.-S. Beignon et al., “Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells,” Journal of Virology, vol. 78, no. 10, pp. 5223–5232, 2004. View at Publisher · View at Google Scholar
  129. J.-F. Fonteneau, M. Gilliet, M. Larsson et al., “Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity,” Blood, vol. 101, no. 9, pp. 3520–3526, 2003. View at Publisher · View at Google Scholar
  130. K. Mahnke, Y. Qian, J. Knop, and A. H. Enk, “Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells,” Blood, vol. 101, no. 12, pp. 4862–4869, 2003. View at Publisher · View at Google Scholar
  131. M. Salio, M. J. Palmowski, A. Atzberger, I. F. Hermans, and V. Cerundolo, “CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens,” The Journal of Experimental Medicine, vol. 199, no. 4, pp. 567–579, 2004. View at Publisher · View at Google Scholar
  132. J. A. Shah, P. A. Darrah, D. R. Ambrozak et al., “Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice,” The Journal of Experimental Medicine, vol. 198, no. 2, pp. 281–291, 2003. View at Publisher · View at Google Scholar
  133. B. Pulendran and R. A. Seder, “Host-pathogen interactions in the 21st century,” Current Opinion in Immunology, vol. 17, no. 4, pp. 335–337, 2005. View at Publisher · View at Google Scholar
  134. M. A. Degli-Esposti and M. J. Smyth, “Close encounters of different kinds: dendritic cells and NK cells take centre stage,” Nature Reviews Immunology, vol. 5, no. 2, pp. 112–124, 2005. View at Publisher · View at Google Scholar
  135. C. Pasare and R. Medzhitov, “Toll-like receptors: linking innate and adaptive immunity,” Advances in Experimental Medicine and Biology, vol. 560, pp. 11–18, 2005. View at Publisher · View at Google Scholar
  136. C. Münz, R. M. Steinman, and S. Fujii, “Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity,” The Journal of Experimental Medicine, vol. 202, no. 2, pp. 203–207, 2005. View at Publisher · View at Google Scholar
  137. K. Evel-Kabler and S.-Y. Chen, “Dendritic cell-based tumor vaccines and antigen presentation attenuators,” Molecular Therapy, vol. 13, no. 5, pp. 850–858, 2006. View at Publisher · View at Google Scholar
  138. H. J. Bontkes, J. J. Ruizendaal, D. Kramer, C. J. L. M. Meijer, and E. Hooijberg, “Plasmacytoid dendritic cells are present in cervical carcinoma and become activated by human papillomavirus type 16 virus-like particles,” Gynecologic Oncology, vol. 96, no. 3, pp. 897–901, 2005. View at Publisher · View at Google Scholar
  139. A. Faith, E. Peek, J. McDonald et al., “Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses,” American Journal of Respiratory Cell and Molecular Biology, vol. 36, no. 3, pp. 360–367, 2007. View at Publisher · View at Google Scholar
  140. A. S. Lonsdorf, H. Kuekrek, B. V. Stern, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann, “Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity,” The Journal of Immunology, vol. 171, no. 8, pp. 3941–3946, 2003. View at Google Scholar
  141. D. N. Sauder, “Imiquimod: modes of action,” British Journal of Dermatology, vol. 149, supplement 66, pp. 5–8, 2003. View at Publisher · View at Google Scholar
  142. R. L. Paquette, N. C. Hsu, S. M. Kiertscher et al., “Interferon-a and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells,” Journal of Leukocyte Biology, vol. 64, no. 3, pp. 358–367, 1998. View at Google Scholar
  143. T. Luft, K. C. Pang, E. Thomas et al., “Type I IFNs enhance the terminal differentiation of dendritic cells,” The Journal of Immunology, vol. 161, no. 4, pp. 1947–1953, 1998. View at Google Scholar
  144. S. M. Santini, C. Lapenta, M. Logozzi et al., “Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice,” The Journal of Experimental Medicine, vol. 191, no. 10, pp. 1777–1788, 2000. View at Publisher · View at Google Scholar
  145. P. Blanco, A. K. Palucka, M. Gill, V. Pascual, and J. Banchereau, “Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus,” Science, vol. 294, no. 5546, pp. 1540–1543, 2001. View at Publisher · View at Google Scholar
  146. D. Gabrilovich, “Mechanisms and functional significance of tumour-induced dendritic-cell defects,” Nature Reviews Immunology, vol. 4, no. 12, pp. 941–952, 2004. View at Publisher · View at Google Scholar
  147. S. Benkő, Z. Magyarics, A. Szabó, and É. Rajnavölgyi, “Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors,” Biological Chemistry, vol. 389, no. 5, pp. 469–485, 2008. View at Publisher · View at Google Scholar