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Dendritic Cells In Vivo: A Key Target for a New Vaccine Science

2008; Cell Press; Volume: 29; Issue: 3 Linguagem: Inglês

10.1016/j.immuni.2008.08.001

1097-4180

Ralph M. Steinman,

T-cell and B-cell Immunology

Dendritic cells (DCs) are the antigen presenting cells that initiate and regulate immunity. By studying these cells in vivo, we will be able to move beyond standard approaches and design vaccines that directly harness the elaborate properties of DCs to control immunity. Dendritic cells (DCs) are the antigen presenting cells that initiate and regulate immunity. By studying these cells in vivo, we will be able to move beyond standard approaches and design vaccines that directly harness the elaborate properties of DCs to control immunity. “The challenge for us as immunologists is to understand how the various elements work and fit together, and then to develop innovative solutions that do better than nature…. Immunity ranks with the most complex of complex systems, along with neurobiology and climate change.” P.C. Doherty and S.J. Turner, Immunity 27: 363–365 The traditional vaccines that we know induce immunity against specific microbial antigens and prevent infectious diseases. These vaccines are a major success story and emanate in large part from the discoveries of Louis Pasteur. His first vaccine against chicken cholera was created in 1879, and his most famous vaccine against human rabies was created in 1885 (Dubos, 1988Dubos R. Pasteur and Modern Science.Second Edition. Science Tech Publishers, Madison, WI1988Crossref Google Scholar). Pasteur's research was based on the science of microbiology, i.e., his discovery that distinct microbes are the causes of disease and that an attenuated microbe can induce long-lived protection against infection by the nonattenuated form of that organism. These breakthroughs occurred before there was any clear understanding of vaccine immunity, which began with the discovery of antibodies by von Behring and Kitasato in the 1890s. After the great advances in immunology during the twentieth century, a new vaccine era has finally arrived on the basis of key immune principles. Vaccines can be defined as formulations that induce specific, nontoxic, and long-lasting immune responses to prevent or treat disease. The new vaccines that immunological research can now develop will deliver the relevant antigens and adjuvants (substances that work with antigens to either enhance or silence immunity) to redirect the immune system for the individual's benefit (Pulendran and Ahmed, 2006Pulendran B. Ahmed R. Translating innate immunity into immunological memory: Implications for vaccine development.Cell. 2006; 124: 849-863Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar) (Figure 1). The dendritic cell (DC) biology that is described in this issue of Immunity provides a foundation on which to create vaccines that not only induce protection against microbes but also deal with cancer (see Melief, 2008Melief C.J.M. Cancer immunotherapy by dendritic cells.Immunity. 2008; 29 (this issue): 372-383Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar), autoimmunity, and allergy (see Belkaid and Oldenhove, 2008Belkaid Y. Oldenhove G. Tuning microenvironments: Induction of regulatory T cells by dendritic cells.Immunity. 2008; 29 (this issue): 362-371Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Here, I will discuss four features of DCs that establish their central role in developing new vaccine strategies: location, antigen handling, maturation, and subsets. As Doherty and Turner write in the introductory quotation, vaccine biology compels us to pull these features of DCs together and “develop innovative solutions that do better than nature.” In the past, emphasis has been placed on the capacity of DCs to pick up antigens in the periphery, including vaccines at an injection site, and then migrate from peripheral tissues to the T cell areas of lymphoid organs to initiate immunity. The underlying biology is elegant (see Alvarez et al., 2008Alvarez D. Vollmann E.H. von Andrian U.H. Mechanisms and consequences of dendritic cell migration.Immunity. 2008; 29 (this issue): 325-342Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, this issue), yet more information is needed on the types of DCs that pick up vaccine antigens at an injection site, such as skin or muscle, and initiate immunity. Now additional origins of DCs are apparent (Shortman and Naik, 2007Shortman K. Naik S.H. Steady-state and inflammatory dendritic-cell development.Nat. Rev. Immunol. 2007; 7: 19-30Crossref PubMed Scopus (925) Google Scholar) (see López-Bravo and Ardavín, 2008López-Bravo M. Ardavín C. In vivo induction of immune responses to pathogens by conventional dendritic cells.Immunity. 2008; 29 (this issue): 343-351Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, this issue). In the steady state, most DCs in lymphoid organs actually arise from a blood precursor (Fogg et al., 2006Fogg D.K. Sibon C. Miled C. Jung S. Aucouturier P. Littman D.R. Cumano A. Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells.Science. 2006; 311: 83-87Crossref PubMed Scopus (732) Google Scholar, Liu et al., 2007Liu K. Waskow C. Liu X. Yao K. Hoh J. Nussenzweig M. Origin of dendritic cells in peripheral lymphoid organs of mice.Nat. Immunol. 2007; 8: 578-583Crossref PubMed Scopus (330) Google Scholar). These precursors can proliferate in the lymphoid organ, a process driven by flt-3 ligand (Waskow et al., 2008Waskow C. Liu K. Darrasse-Jeze G. Guermonprez P. Ginhoux F. Merad M. Shengelia T. Yao K. Nussenzweig M. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues.Nat. Immunol. 2008; 9: 676-683Crossref PubMed Scopus (417) Google Scholar). Another potentially major source of DCs is monocytes. Monocyte-derived DCs accumulate in lymphoid tissues during some infections, e.g., Leishmania major (Leon et al., 2007Leon B. Lopez-Bravo M. Ardavin C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania.Immunity. 2007; 26: 519-531Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar). Learning how to mobilize and access these other reservoirs of DCs in vivo could enhance the quality and efficacy of vaccine-induced immunity. Effective mucosal immunity or resistance at body surfaces is a major hurdle for vaccine development, probably because mucosal surfaces are specialized to sustain nonreactivity to all the innocuous antigens within commensal microorganisms and the proteins in the air we breathe and the foods we eat. HIV-1 vaccines for example will probably need to induce mucosal immunity because this virus is most often transmitted via a mucosal route and quickly leads to a rapid loss of T cells in the intestine (Brenchley et al., 2004Brenchley J.M. Schacker T.W. Ruff L.E. Price D.A. Taylor J.H. Beilman G.J. Nguyen P.L. Khoruts A. Larson M. Haase A.T. Douek D.C. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.J. Exp. Med. 2004; 200: 749-759Crossref PubMed Scopus (1350) Google Scholar, Mehandru et al., 2004Mehandru S. Poles M.A. Tenner-Racz K. Horowitz A. Hurley A. Hogan C. Boden D. Racz P. Markowitz M. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract.J. Exp. Med. 2004; 200: 761-770Crossref PubMed Scopus (852) Google Scholar). DCs are uniquely located beneath the epithelium at several mucosal surfaces, such as the airway, intestine, and stomach. Intravital microscopy has helped reveal that these cells insinuate their dendritic processes between epithelial cells to enter the mucosal lumen (Chieppa et al., 2006Chieppa M. Rescigno M. Huang A.Y.C. Germain R.N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement.J. Exp. Med. 2006; 203: 2841-2852Crossref PubMed Scopus (545) Google Scholar, Niess et al., 2005Niess J.H. Brand S. Gu X. Landsman L. Jung S. McCormick B.A. Vyas J.M. Boes M. Ploegh H.L. Fox J.G. et al.CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance.Science. 2005; 307: 254-258Crossref PubMed Scopus (1217) Google Scholar). A critical goal is to determine whether vaccines can be designed to access these mucosal DCs to bring about better mucosal immunity. Depending upon the medical condition under investigation, desirable mucosal vaccines need to induce both antibodies and T cells that block infection at the site of pathogen entry, or alternatively activate suppressor T cells (“regulatory T cells”), which have the potential to block the inflammatory and allergic diseases at mucosal surfaces (see Belkaid, 2008). One gap in current knowledge relates to antigen and adjuvant delivery to DCs associated with organized mucosal lymphoid tissues such as Peyer's patches. Because the latter are covered by a distinctive epithelium rich in antigen-transporting M cells, receptors on these M cells, if ligated, could improve vaccine delivery to the DCs that lie underneath (Nochi et al., 2007Nochi T. Yuki Y. Matsumura A. Mejima M. Terahara K. Kim D.Y. Fukuyama S. Iwatsuki-Horimoto K. Kawaoka Y. Kohda T. et al.A novel M cell-specific carbohydrate-targeted mucosal vaccine effectively induces antigen-specific immune responses.J. Exp. Med. 2007; 204: 2789-2796Crossref PubMed Scopus (151) Google Scholar). A hallmark of DC location is their abundance in lymphoid tissues, particularly the T cell areas (Alvarez et al., 2008Alvarez D. Vollmann E.H. von Andrian U.H. Mechanisms and consequences of dendritic cell migration.Immunity. 2008; 29 (this issue): 325-342Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). Numerically, DCs represent a tiny fraction of total cells, but their processes constantly probe the environment, forming a vast and labyrinthine network through which lymphocytes must pass (Lindquist et al., 2004Lindquist R.L. Shakhar G. Dudziak D. Wardemann H. Eisenreich T. Dustin M.L. Nussenzweig M.C. Visualizing dendritic cell networks in vivo.Nat. Immunol. 2004; 5: 1243-1250Crossref PubMed Scopus (625) Google Scholar). This sets the stage for the selection of rare but specific clones of lymphocytes during the initial steps of vaccination. It is now feasible to target vaccine antigens directly to these numerous DCs in the T cell areas and modulate their function with adjuvants (Bonifaz et al., 2004Bonifaz L.C. Bonnyay D.P. Charalambous A. Darguste D.I. Fujii S. Soares H. Brimnes M.K. Moltedo B. Moran T.M. Steinman R.M. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.J. Exp. Med. 2004; 199: 815-824Crossref PubMed Scopus (730) Google Scholar, Boscardin et al., 2006Boscardin S.B. Hafalla J.C.R. Kamphorst A.O. Malilamani R.F. Zebroski H.A. Rai U. Morrot A. Zavala F. Steinman R.M. Nussenzweig R.S. Nussenzweig M.C. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses.J. Exp. Med. 2006; 203: 599-606Crossref PubMed Scopus (202) Google Scholar, Trumpfheller et al., 2008Trumpfheller C. Caskey M. Nchinda G. Longhi M.P. Mizenina O. Huang Y. Schlesinger S.J. Colonna M. Steinman R.M. The microbial mimic polyIC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine.Proc. Natl. Acad. Sci. USA. 2008; 105: 2574-2579Crossref PubMed Scopus (234) Google Scholar, Trumpfheller et al., 2006Trumpfheller C. Finke J.S. Lopez C.B. Moran T.M. Moltedo B. Soares H. Huang Y. Schlesinger S.J. Park C.G. Nussenzweig M.C. et al.Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine.J. Exp. Med. 2006; 203: 607-617Crossref PubMed Scopus (183) Google Scholar). Because of the molecular identification of the DEC-205 (CD205) antigen uptake receptor on DCs (Jiang et al., 1995Jiang W. Swiggard W.J. Heufler C. Peng M. Mirza A. Steinman R.M. Nussenzweig M.C. The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing.Nature. 1995; 375: 151-155Crossref PubMed Scopus (779) Google Scholar), it has become apparent that these cells express a plethora of such receptors, often lectins. These molecules deliver antigens to processing compartments, leading to the presentation of antigen fragments on MHC and CD1 molecules (see Villadangos and Young, 2008Villadangos J.A. Young L. Plasmacytoid dendritic cell antigen presentation in vivo.Immunity. 2008; 29 (this issue): 352-361Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). Endocytic receptors in some cases also signal DC activation or deactivation (Robinson et al., 2006Robinson M.J. Sancho D. Slack E.C. Leibundgut-Landmann S. Sousa C.R. Myeloid C-type lectins in innate immunity.Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (386) Google Scholar). Although DCs are able to capture antigens as solutes in endocytic vacuoles (“pinocytosis”), the identification of uptake receptors changes the study of DC biology in vivo and opens new possibilities for efficient vaccine delivery to DCs and vaccine design. By identifying specific ligands for antigen uptake receptors on DCs, or by using monoclonal anti-receptor antibodies as surrogate ligands, one can efficiently target vaccine antigens to DCs or their subsets (see below) in vivo (Hawiger et al., 2001Hawiger D. Inaba K. Dorsett Y. Guo M. Mahnke K. Rivera M. Ravetch J.V. Steinman R.M. Nussenzweig M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.J. Exp. Med. 2001; 194: 769-780Crossref PubMed Scopus (1460) Google Scholar). Retroviral vectors gain improved immunogenicity if the envelope is engineered to target the DC-SIGN (CD209) receptor on DCs (Yang et al., 2008Yang L. Yang H. Rideout K. Cho T. Joo K.I. Ziegler L. Elliot A. Walls A. Yu D. Baltimore D. Wang P. Engineered lentivector targeting of dendritic cells for in vivo immunization.Nat. Biotechnol. 2008; 26: 326-334Crossref PubMed Scopus (163) Google Scholar). The efficacy of HIV DNA vaccines can be improved by targeting to DEC-205 (Nchinda et al., 2008Nchinda G. Kuroiwa J. Oks M. Trumpfheller C. Park C.G. Huang Y. Hannaman D. Schlesinger S.J. Mizenina O. Nussenzweig M.C. et al.The efficacy of DNA vaccination is enhanced by targeting the encoded protein to dendritic cells.J. Clin. Invest. 2008; 118: 1427-1436Crossref PubMed Scopus (150) Google Scholar). Low doses of protein-based vaccines have also been targeted to DEC-205 along with poly IC as adjuvant. This leads to a large T helper 1 (Th1) cell type of T cell response, whereas targeting to the DCIR2 receptor on another subset of DCs allows both IFN-γ and IL-4 to be induced (Soares et al., 2007Soares H. Waechter H. Glaichenhaus N. Mougneau E. Yagita H. Mizenina O. Dudziak D. Nussenzweig M.C. Steinman R.M. A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12-independent but CD70-dependent mechanism in vivo.J. Exp. Med. 2007; 204: 1095-1106Crossref PubMed Scopus (232) Google Scholar, Trumpfheller et al., 2008Trumpfheller C. Caskey M. Nchinda G. Longhi M.P. Mizenina O. Huang Y. Schlesinger S.J. Colonna M. Steinman R.M. The microbial mimic polyIC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine.Proc. Natl. Acad. Sci. USA. 2008; 105: 2574-2579Crossref PubMed Scopus (234) Google Scholar). Receptor targeting not only enhances antigen uptake and processing a hundred fold but also facilitates research on DCs and receptor function in vivo without the need to isolate the cells (Hawiger et al., 2001Hawiger D. Inaba K. Dorsett Y. Guo M. Mahnke K. Rivera M. Ravetch J.V. Steinman R.M. Nussenzweig M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.J. Exp. Med. 2001; 194: 769-780Crossref PubMed Scopus (1460) Google Scholar)(Bonifaz et al., 2004Bonifaz L.C. Bonnyay D.P. Charalambous A. Darguste D.I. Fujii S. Soares H. Brimnes M.K. Moltedo B. Moran T.M. Steinman R.M. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.J. Exp. Med. 2004; 199: 815-824Crossref PubMed Scopus (730) Google Scholar). Another major hurdle for vaccine design is “crosspresentation.” Nonreplicating vaccines, e.g., the Salk inactivated viral vaccine, as well as protein vaccines, e.g., the diphtheria-pertussis-tetanus (DPT) vaccine, are capable of inducing antibody and CD4+ T cell immunity, sufficient in quantity and quality to provide protection against the polio virus and DPT toxins, respectively. However, in order for protein-based vaccines to elicit resistance to HIV and cancer, a nonreplicating form of an antigen needs to elicit MHC-class-I-restricted, CD8+ or cytotoxic T cells. Typically, MHC I presentation requires microbial replication and antigen synthesis in an infected cell; e.g., attenuated viral vectors can elicit CD8+ cytotoxic T cells, but they also elicit antivector immunity that can compromise the efficacy of booster doses of vaccine. Crosspresentation could overcome these hurdles because it provides a route for “exogenous” vaccine proteins to be processed and to gain access to MHC I. Mechanisms are under study (Kasturi and Pulendran, 2008Kasturi S.P. Pulendran B. Cross-presentation: Avoiding trafficking chaos?.Nat. Immunol. 2008; 9: 461-463Crossref PubMed Scopus (18) Google Scholar); the latest concept is that there are special endosomal compartments where internalized antigens are crosspresented (Burgdorf et al., 2008Burgdorf S. Scholz C. Kautz A. Tampe R. Kurts C. Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation.Nat. Immunol. 2008; 9: 558-566Crossref PubMed Scopus (318) Google Scholar, Di Pucchio et al., 2008Di Pucchio T. Chatterjee B. Smed-Sorensen A. Clayton S. Palazzo A. Montes M. Xue Y. Mellman I. Banchereau J. Connolly J.E. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I.Nat. Immunol. 2008; 9: 551-557Crossref PubMed Scopus (214) Google Scholar). Certain receptors may be specialized to traverse the crosspresentation pathway, such as Fc receptors for antibody complexes (Dhodapkar et al., 2002aDhodapkar K.M. Krasovsky J. Williamson B. Dhodapkar M.V. Anti-tumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells.J. Exp. Med. 2002; 195: 125-133Crossref PubMed Scopus (310) Google Scholar, Regnault et al., 1999Regnault A. Lankar D. Lacabanne V. Rodriguez A. Thery C. Rescigno M. Saito T. Verbeek S. Bonnerot C. Ricciardi-Castagnoli P. Amigorena S. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization.J. Exp. Med. 1999; 189: 371-380Crossref PubMed Scopus (765) Google Scholar), receptors for dying cells (den Haan et al., 2000den Haan J.M. Lehar S.M. Bevan M.J. CD8+ but not CD8- dendritic cells cross-prime cytotoxic T cells in vivo.J. Exp. Med. 2000; 192: 1685-1696Crossref PubMed Scopus (977) Google Scholar, Dhodapkar et al., 2002bDhodapkar M.V. Krasovsky J. Olson K. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells.Proc. Natl. Acad. Sci. USA. 2002; 99: 13009-13013Crossref PubMed Scopus (129) Google Scholar, Iyoda et al., 2002Iyoda T. Shimoyama S. Liu K. Omatsu Y. Akiyama Y. Maeda Y. Takahara K. Steinman R.M. Inaba K. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo.J. Exp. Med. 2002; 195: 1289-1302Crossref PubMed Scopus (507) Google Scholar), and certain C-type lectin receptors such as DEC-205 (Bonifaz et al., 2004Bonifaz L.C. Bonnyay D.P. Charalambous A. Darguste D.I. Fujii S. Soares H. Brimnes M.K. Moltedo B. Moran T.M. Steinman R.M. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.J. Exp. Med. 2004; 199: 815-824Crossref PubMed Scopus (730) Google Scholar, Bozzacco et al., 2007Bozzacco L. Trumpfheller C. Siegal F.P. Mehandru S. Markowitz M. Carrington M. Nussenzweig M.C. Piperno A.G. Steinman R.M. DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes.Proc. Natl. Acad. Sci. USA. 2007; 104: 1289-1294Crossref PubMed Scopus (186) Google Scholar). Targeting these receptors with vaccines may help to overcome the crosspresentation hurdle during vaccination. Nonetheless, I urge the field to move beyond the dominant use of ovalbumin in C57Bl/6 mice as the model antigen for these studies because it is orders of magnitude more sensitive than the antigens that need to be crosspresented to create effective vaccines. Ovalbumin may be distorting the standards for discovering safe, defined, protein-based vaccines. The most intricate feature of DCs is their capacity to differentiate or mature along many different lines. This is driven by many different types of stimuli including (1) microbial ligands for pattern recognition receptors, (2) innate lymphocytes, (3) immune complexes acting on Fc receptors, and (4) additional environmental and endogenous stimuli termed “alarmins.” Maturing DCs, depending on the stimulus as well as environmental factors affecting lymphocytes, then determine the type of response, which can be either immunogenic, providing resistance, or tolerogenic, silencing an immune response. One sphere of immunity that is particularly sensitive to the type of stimulus encountered by DCs is CD4+ helper T cell differentiation. The specific pathway followed by CD4+ T cells, whether it involves Th1, Th2, Th17, Tf, Tr1, or Treg cell differentiation, is significantly governed by DCs. A major challenge is to understand how vaccine adjuvants influence DC maturation in vivo, so that the resulting immunity will appropriately resist a particular pathogen or disease. Two important areas of science are pattern recognition receptors and DC subsets (next) (Agrawal et al., 2003Agrawal S. Agrawal A. Doughty B. Gerwitz A. Blenis J. Van Dyke T. Pulendran B. Different toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos.J. Immunol. 2003; 171: 4984-4989PubMed Google Scholar, Shah et al., 2003Shah J.A. Darrah P.A. Ambrozak D.R. Turon T.N. Mendez S. Kirman J. Wu C.Y. Glaichenhaus N. Seder R.A. Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice.J. Exp. Med. 2003; 198: 281-291Crossref PubMed Scopus (66) Google Scholar). Synthetic double-stranded RNA, poly IC, is recognized by TLR3 and MDA-5 receptors, and it can polarize CD4+ T cells along a Th1 cell pathway when delivered with antigens to the CD205+ DC subset (Soares et al., 2007Soares H. Waechter H. Glaichenhaus N. Mougneau E. Yagita H. Mizenina O. Dudziak D. Nussenzweig M.C. Steinman R.M. A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12-independent but CD70-dependent mechanism in vivo.J. Exp. Med. 2007; 204: 1095-1106Crossref PubMed Scopus (232) Google Scholar, Trumpfheller et al., 2008Trumpfheller C. Caskey M. Nchinda G. Longhi M.P. Mizenina O. Huang Y. Schlesinger S.J. Colonna M. Steinman R.M. The microbial mimic polyIC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine.Proc. Natl. Acad. Sci. USA. 2008; 105: 2574-2579Crossref PubMed Scopus (234) Google Scholar). TLR7-TLR8 and TLR9 ligands also can serve as adjuvants for responses by IFN-γ-producing T cells (Wille-Reece et al., 2006Wille-Reece U. Flynn B.J. Lore K. Koup R.A. Miles A.P. Saul A. Kedl R.M. Mattapallil J.J. Weiss W.R. Roederer M. Seder R.A. Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates.J. Exp. Med. 2006; 203: 1249-1258Crossref PubMed Scopus (235) Google Scholar). In contrast, ligands for the dectin receptor, when applied to bone-marrow-derived DCs, lead to IL-2 and IL-10 production and seem to favor Th17 cell differentiation (LeibundGut-Landmann et al., 2007LeibundGut-Landmann S. Gross O. Robinson M.J. Osorio F. Slack E.C. Tsoni S.V. Schweighoffer E. Tybulewicz V. Brown G.D. Ruland J. Reis e Sousa C. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.Nat. Immunol. 2007; 8: 630-638Crossref PubMed Scopus (868) Google Scholar). Ligation of c-kit and TSLP receptors allows DCs to induce Th2 cell responses, a process that takes place in the presence of certain allergens such as the house dust-mite allergen (Krishnamoorthy et al., 2008Krishnamoorthy N. Oriss T.B. Paglia M. Fei M. Yarlagadda M. Vanhaesebroeck B. Ray A. Ray P. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma.Nat. Med. 2008; 14: 565-573Crossref PubMed Scopus (163) Google Scholar, Soumelis et al., 2002Soumelis V. Reche P.A. Kanzler H. Yuan W. Edward G. Homey B. Gilliet M. Ho S. Antonenko S. Lauerma A. et al.Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP.Nat. Immunol. 2002; 3: 673-680Crossref PubMed Scopus (327) Google Scholar). These observations set the stage to design vaccines that direct the antigen-presenting DCs and/or the responding T cells to develop selected types of immunity; e.g., Th1 T cells help resist many viruses and tumors, Th2 cells mediate parasitic infections, and Th17 cells respond to certain extracellular bacteria and fungi. An exciting new area will be to design vaccines to specifically silence unwanted immune reactions by taking advantage of DC programs that lead to tolerance. DCs can induce tolerance by deleting or silencing T cells (Brimnes et al., 2003Brimnes M.K. Bonifaz L. Steinman R.M. Moran T.M. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein.J. Exp. Med. 2003; 198: 133-144Crossref PubMed Scopus (156) Google Scholar, Hawiger et al., 2004Hawiger D. Masilamani R.F. Bettelli E. Kuchroo V.K. Nussenzweig M.C. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo.Immunity. 2004; 20: 695-705Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar), but they can also induce differentiation of suppressive T cells, e.g., IL-10 producers (Levings et al., 2005Levings M.K. Gregori S. Tresoldi E. Cazzaniga S. Bonini C. Roncarolo M.G. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells.Blood. 2005; 105: 1162-1169Crossref PubMed Scopus (390) Google Scholar, Macdonald et al., 2005Macdonald K.P. Rowe V. Clouston A.D. Welply J.K. Kuns R.D. Ferrara J.L. Thomas R. Hill G.R. Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells.J. Immunol. 2005; 174: 1841-1850PubMed Google Scholar), and foxp3+ Treg cells (Kretschmer et al., 2005Kretschmer K. Apostolou I. Hawiger D. Khazaie K. Nussenzweig M.C. von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen.Nat. Immunol. 2005; 6: 1219-1227Crossref PubMed Scopus (993) Google Scholar, Luo et al., 2007Luo X. Tarbell K.V. Yang H. Pothoven K. Bailey S.L. Ding R. Steinman R.M. Suthanthiran M. Dendritic cells with TGF-β1 differentiate naive CD4+CD25− T cells into islet-protective Foxp3+ regulatory T cells.Proc. Natl. Acad. Sci. USA. 2007; 104: 2821-2826Crossref PubMed Scopus (192) Google Scholar). Environmental cytokines such as IL-10 and TGF-β, as well as vitamin A, can be critical. The CD8+ or CD205+ subset of DCs in mice produces more TGF-β (Wang et al., 2008Wang L. Pino-Lagos K. de Vries V.C. Guleria I. Sayegh M.H. Noelle R.J. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells.Proc. Natl. Acad. Sci. USA. 2008; 105: 9331-9336Crossref PubMed Scopus (292) Google Scholar; our unpublished data) and also metabolizes vitamin A to retinoic acid; TGF-β and retinoic acid are cofactors for Treg cell development (Coombes et al., 2007Coombes J.L. Siddiqui K.R. Arancibia-Carcamo C.V. Hall J. Sun C.M. Belkaid Y. Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β- and retinoic acid-dependent mechanism.J. Exp. Med. 2007; 204: 1757-1764Crossref PubMed Scopus (2038) Google Scholar, Sun et al., 2007Sun C.M. Hall J.A. Blank R.B. Bouladoux N. Oukka M. Mora J.R. Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.J. Exp. Med. 2007; 204: 1775-1785Crossref PubMed Scopus (1422) Google Scholar). A different pathway involves the E-cadherin that DCs use to bind other cells or other DCs; when the DCs detach, the E-cadherin signals upregulation of the lymph-node-homing receptor CCR7 and production of tolerizing amounts of IL-10 (Jiang et al., 2007Jiang A. Bloom O. Ono S. Cui W. Unternaehrer J. Jiang S. Whitney J.A. Connolly J. Banchereau J. Mellman I. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation.Immunity. 2007; 27: 610-624Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). In yet another route (and there will be many others!), ligation of select ILT molecules on DCs makes them tolerogenic (Liang et