Dendritic Cells: Translating Innate to Adaptive Immunity

  • R. M. Steinman
  • H. Hemmi
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 311)


The innate immune system provides many ways to quickly resist infection. The twobest-studieddefenses indendritic cells (DCs) are the productionof protective cytokines—like interleukin (IL)-12 and type I interferons—and the activation and expansion of innate lymphocytes. IL-12 and type I interferons influence distinct steps in the adaptive immune response of lymphocytes, including the polarization of Thelper type 1 (Th1)CD4+ T cells, thedevelopment of cytolytic T cells andmemory, and the antibody response. DCs havemany other innate features that do not by themselves provide innate resistance but are critical for the induction of adaptive immunity. We have emphasized three intricate and innate properties of DCs that account for their sentinel and sensor roles in the immune system: (1) special mechanisms for antigen capture and processing, (2) the capacity tomigrate to defined sites in lymphoid organs, especially the T cell areas, to initiate immunity, and (3) their rapid differentiation or maturation in response to a variety of stimuli ranging from Toll-like receptor (TLR) ligands to many other nonmicrobial factors such as cytokines, innate lymphocytes, and immune complexes. The combination of innate defenses and innate physiological properties allows DCs to serve as amajor link between innate and adaptive immunity. DCs and their subsets contribute to many subjects that are ripe for study including memory, B cell responses, mucosal immunity, tolerance, and vaccine design. DC biology should continue to be helpful in understanding pathogenesis and protection in the setting of prevalent clinical problems.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pulendran B, Palucka K, Banchereau J (2001) Sensing pathogens and tuning immune responses. Science 293:253–256PubMedGoogle Scholar
  2. 2.
    Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6:1382–1387PubMedGoogle Scholar
  3. 3.
    Pulendran B (2005) Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol 174:2457–2465PubMedGoogle Scholar
  4. 4.
    Inaba K, Turley S, Yamaide F, Iyoda T, Mahnke K, Inaba M, Pack M, Subklewe M, Sauter B, Sheff D, Albert M, Bhardwaj N, Mellman I, Steinman RM (1998) Efficient presentation of phagocytosed cellular fragments on the MHC class II products of dendritic cells. J Exp Med 188:2163–2173PubMedGoogle Scholar
  5. 5.
    Iyoda T, Shimoyama S, Liu K, Omatsu Y, Maeda Y, Takahara K, Akiyama Y, Steinman RM, Inaba K (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195:1289–1302PubMedGoogle Scholar
  6. 6.
    Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, Germain RN, Sher A (1997) In vivo microbial stimulation induces rapid CD40L-independent production of IL-12 by dendritic cells and their re-distribution to T cell areas. J Exp Med 186:1819–1829PubMedGoogle Scholar
  7. 7.
    Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, Briere F, Trinchieri G, Biron CA (2002) Interferon α/β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med 195:517–528PubMedGoogle Scholar
  8. 8.
    Le Bon A, Tough DF (2002) Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14:432–436PubMedGoogle Scholar
  9. 9.
    Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146PubMedGoogle Scholar
  10. 10.
    Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405–411PubMedGoogle Scholar
  11. 11.
    Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195:327–333PubMedGoogle Scholar
  12. 12.
    Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C (2002) Human dendritic cells activate resting NK cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195:343–351PubMedGoogle Scholar
  13. 13.
    Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM (2003) Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a co-administered protein. J Exp Med 198:267–279PubMedGoogle Scholar
  14. 14.
    Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171:5140–5147PubMedGoogle Scholar
  15. 15.
    Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT, Brenner MB (2002) CD1-mediated γ/δ T cell maturation of dendritic cells. J Exp Med 196:1575–1584PubMedGoogle Scholar
  16. 16.
    Munz C, Steinman RM, Fujii S (2005) Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med 202:203–207PubMedGoogle Scholar
  17. 17.
    Fathman CG, Handwerger BS, Sachs DA (1974) Evidence for a role of Ir-associated alloantigens in mixed lymphocyte culture stimulation. J Exp Med 140:853PubMedGoogle Scholar
  18. 18.
    Hammerling GJ, Mauve G, Goldberg E, McDevitt HO (1975) Tissue distribution of Ia antigens: Ia on spermatozoa, macrophages and epidermal cells. Immunogenetics 1:428Google Scholar
  19. 19.
    Nussenzweig MC, Steinman RM, Witmer MD, Gutchinov B (1982) A monoclonal antibody specific for mouse dendritic cells. Proc Natl Acad Sci USA 79:161–165PubMedGoogle Scholar
  20. 20.
    Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC (1983) Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med 157:613–627PubMedGoogle Scholar
  21. 21.
    Kraal G, Breel M, Janse M, Bruin G (1986) Langerhans cells, veiled cells, and interdigitating cells in the mouse recognized by a monoclonal antibody. J Exp Med 163:981–997PubMedGoogle Scholar
  22. 22.
    Hart DNJ, Fabre JW (1981) Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med 154:347–361PubMedGoogle Scholar
  23. 23.
    Klinkert WEF, Labadie JH, Bowers WE (1982) Accessory and stimulating properties of dendritic cells and macrophages isolated from various rat tissues. J Exp Med 156:1–19PubMedGoogle Scholar
  24. 24.
    Van Voorhis WC, Valinsky J, Hoffman E, Luban J, Hair LS, Steinman RM (1983) Relative efficacy of human monocytes and dendritic cells as accessory cells for T cell replication. J Exp Med 158:174–191PubMedGoogle Scholar
  25. 25.
    Spalding D, Koopman WJ, Eldridge JH, McGhee JR, Steinman RM (1983) Accessory cells in murine Peyer’s patch. I. Identification and enrichment of a functional dendritic cell. J Exp Med 157:1646–1659PubMedGoogle Scholar
  26. 26.
    Hart DN, McKenzie JL (1988) Isolation and characterization of human tonsil dendritic cells. J Exp Med 168:157–170PubMedGoogle Scholar
  27. 27.
    Witmer MD, Steinman RM (1984) The anatomy of peripheral lymphoid organs with emphasis on accessory cells: light microscopic, immunocytochemical studies of mouse spleen, lymph node and Peyer’s patch. Am J Anat 170:465–481PubMedGoogle Scholar
  28. 28.
    Kelly RH, Balfour BM, Armstrong JA, Griffiths S (1978) Functional anatomy of lymph nodes. II. Peripheral lymph-borne mononuclear cells. Anat Rec 190:5–21PubMedGoogle Scholar
  29. 29.
    Drexhage HA, Mullink H, de Groot J, Clarke J, Balfour BM (1979) A study of cells present in peripheral lymph of pigs with special reference to a type of cell resembling the Langerhans cells. Cell Tissue Res 202:407–430PubMedGoogle Scholar
  30. 30.
    Knight SC, Balfour BM, O’Brien J, Buttifant L, Sumerska T, Clark J (1982) Role of veiled cells in lymphocyte activation. Eur J Immunol 12:1057–1060PubMedGoogle Scholar
  31. 31.
    Pugh CW, MacPherson GG, Steer HW (1983) Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med 157:1758–1779PubMedGoogle Scholar
  32. 32.
    Bujdoso R, Hopkins J, Dutia BM, Young P, McConnell I (1989) Characterization of sheep afferent lymph dendritic cells and their role in antigen carriage. J Exp Med 170:1285–1302PubMedGoogle Scholar
  33. 33.
    Randolph GJ, Angeli V, Swartz MA (2005) Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5:617–628PubMedGoogle Scholar
  34. 34.
    Romani N, Turley S, Pypaert M, Ebersold M, Mellman I, Schuler G, Steinman RM (2005) Dendritic cells. In: Zucker-Franklin D, Grossi CE (eds) Atlas of blood cells-function and pathology. Arti Grafiche Salea, Milan, pp 449–478Google Scholar
  35. 35.
    Holt PG, Schon-Hegrad MA, Oliver J (1987) MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation activity by endogenous macrophage populations. J Exp Med 167:262–274Google Scholar
  36. 36.
    Holt PG, Schon-Hegrad MA, Oliver J, Holt BJ, McMenamin PG (1990) A contiguous network of dendritic antigen presenting cells within the respiratory epithelium. Int Arch Allergy Appl Immunol 91:155–159PubMedGoogle Scholar
  37. 37.
    Maric I, Holt PG, Perdue MH, Bienenstock J (1996) Class II MHC antigen [Ia]-bearing dendritic cells in the epitheliumof the rat intestine. J Immunol 156:1408–1414PubMedGoogle Scholar
  38. 38.
    Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258PubMedGoogle Scholar
  39. 39.
    Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2:361–367PubMedGoogle Scholar
  40. 40.
    Iwasaki A, Kelsall BL (2000) Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J Exp Med 191:1381–1394PubMedGoogle Scholar
  41. 41.
    Fleeton MN, Contractor N, Leon F, Wetzel JD, Dermody TS, Kelsall BL (2004) Peyer’s patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice. J Exp Med 200:235–245PubMedGoogle Scholar
  42. 42.
    Frankel SS, Wenig BM, Burke AP, Mannan P, Thompson LDR, Abbondanzo SL, Nelson AM, Pope M, Steinman RM (1996) Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science 272:115–117PubMedGoogle Scholar
  43. 43.
    Flores-Langarica A, Meza-Perez S, Calderon-Amador J, Estrada-Garcia T, Mac-Pherson G, Lebecque S, Saeland S, Steinman R, Flores-Romo L (2005) A network of dendritic cells within the muscular layer of the mouse intestine. Proc Natl Acad Sci USA 102:19039–109044PubMedGoogle Scholar
  44. 44.
    Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Ait-Yahia S, Briere F, Zlotnik A, Lebecque S, Caux C (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188:373–386PubMedGoogle Scholar
  45. 45.
    Brimnes MK, Bonifaz L, Steinman RM, Moran TM (2003) 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 198:133–144PubMedGoogle Scholar
  46. 46.
    Liu LM, MacPherson GG (1993) Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo. J Exp Med 177:1299–1307PubMedGoogle Scholar
  47. 47.
    Huang FP, Platt N, Wykes M, Major JR, Powell TJ, Jenkins CD, MacPherson GG (2000) A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med 191:435–442PubMedGoogle Scholar
  48. 48.
    Matsuno K, Ezaki T (2000) Dendritic cell dynamics in the liver and hepatic lymph. Int Rev Cytol 197:83–136PubMedGoogle Scholar
  49. 49.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82PubMedGoogle Scholar
  50. 50.
    Randolph GJ, Sanchez-Schmitz G, Liebman RM, Schakel K (2002) The CD16+ (FcγRIII+) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J Exp Med 196:517–527PubMedGoogle Scholar
  51. 51.
    Qu C, Edwards EW, Tacke F, Angeli V, Llodra J, Sanchez-Schmitz G, Garin A, Haque NS, Peters W, van Rooijen N, Sanchez-Torres C, Bromberg J, Charo IF, Jung S, Lira SA, Randolph GJ (2004) Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med 200:1231–1241PubMedGoogle Scholar
  52. 52.
    Yanagihara S, Komura E, Nagafune J, Watarai H, Yamaguchi Y (1998) EB11/CCR7 is a new member of dendritic cell chemokine receptor that is upregulated upon maturation. J Immunol 161:3096–3102PubMedGoogle Scholar
  53. 53.
    Cyster JG (1999) Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. J Exp Med 189:447–450PubMedGoogle Scholar
  54. 54.
    Martin-Fontecha A, Sebastiani S, Höpken UE, Uguccioni M, Lipp M, Lanzavecchia A, Sallusto F (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198:615–621PubMedGoogle Scholar
  55. 55.
    Pasare C, Medzhitov R (2004) Toll-dependent control mechanisms of CD4 T cell activation. Immunity 21:733–741PubMedGoogle Scholar
  56. 56.
    Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with IL-3 and CD40-ligand. J Exp Med 185:1101–1111PubMedGoogle Scholar
  57. 57.
    Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura M, Ishikawa S, Hasegawa G, Naito M, Asakura H, Matsushima K (2001) Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med 193:35–50PubMedGoogle Scholar
  58. 58.
    Yoneyama H, Matsuno K, Zhang Y, Nishiwaki T, Kitabatake M, Ueha S, Narumi S, Morikawa S, Ezaki T, Lu B, Gerard C, Ishikawa S, Matsushima K (2004) Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int Immunol 16:915–928PubMedGoogle Scholar
  59. 59.
    Larsen CP, Morris PJ, Austyn JM (1990) Migration of dendritic leukocytes from cardiac allografts into host spleens: a novel pathway for initiation of rejection. J Exp Med 171:307–314PubMedGoogle Scholar
  60. 60.
    Steinman RM, Witmer MD (1978) Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci USA 75:5132–5136PubMedGoogle Scholar
  61. 61.
    Kabashima K, Banks TA, Ansel KM, Lu TT, Ware CF, Cyster JG (2005) Intrinsic lymphotoxin-β receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22:439–450PubMedGoogle Scholar
  62. 62.
    Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Engleman EG (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3:1135–1141PubMedGoogle Scholar
  63. 63.
    Bousso P, Robey E (2003) Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol 4:579–585PubMedGoogle Scholar
  64. 64.
    Miller MJ, Safrina O, Parker I, Cahalan MD (2004) Imaging the single cell dynamics of CD4+Tcell activation by dendritic cells in lymph nodes. J Exp Med 200:847–856PubMedGoogle Scholar
  65. 65.
    Mempel TR, Henrickson SE, Von Andrian UH (2004) T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427:154–159PubMedGoogle Scholar
  66. 66.
    Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, Dustin ML, Nussenzweig MC (2004) Visualizing dendritic cell networks in vivo. Nat Immunol 5:1243–1250PubMedGoogle Scholar
  67. 67.
    Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, Nussenzweig MC, Dustin ML (2005) Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat Immunol 6:707–714PubMedGoogle Scholar
  68. 68.
    Zinselmeyer BH, Dempster J, Gurney AM, Wokosin D, Miller M, Ho H, Millington OR, Smith KM, Rush CM, Parker I, Cahalan M, Brewer JM, Garside P (2005) In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance. J Exp Med 201:1815–1823PubMedGoogle Scholar
  69. 69.
    Hawiger D, Inaba K, Dorsett Y, Guo K, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194:769–780PubMedGoogle Scholar
  70. 70.
    Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196:1627–1638PubMedGoogle Scholar
  71. 71.
    Morgan DJ, Kurts C, Kreuwel HT, Holst KL, Heath WR, Sherman LA (1999) Ontogeny of T cell tolerance to peripherally expressed antigens. Proc Natl Acad Sci USA 96:3854–3858PubMedGoogle Scholar
  72. 72.
    Iezzi G, Karjalainen K, Lanzavecchia A (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8:89–95PubMedGoogle Scholar
  73. 73.
    Steinman RM, Cohn ZA (1973) Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 137:1142–1162PubMedGoogle Scholar
  74. 74.
    MacPherson GG, Jenkins CD, Stein MJ, Edwards C (1995) Endotoxin-mediated dendritic cell release from the intestine: characterization of released dendritic cells and TNF dependence. J Immunol 154:1317–1322PubMedGoogle Scholar
  75. 75.
    Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711PubMedGoogle Scholar
  76. 76.
    Schuler G, Steinman RM (1985) Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med 161:526–546PubMedGoogle Scholar
  77. 77.
    Inaba K, Schuler G, Witmer MD, Valinsky J, Atassi B, Steinman RM (1986) The immunologic properties of purified Langerhans cells: distinct requirements for the stimulation of unprimed and sensitized T lymphocytes. J Exp Med 164:605–613PubMedGoogle Scholar
  78. 78.
    Crowley M, Inaba K, Witmer-Pack M, Steinman RM (1989) The cell surface of mouse dendritic cells: FACS analyses of dendritic cells from different tissues including thymus. Cell Immunol 118:108–125PubMedGoogle Scholar
  79. 79.
    Inaba K, Metlay JP, Crowley MT, Steinman RM (1990) Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med 172:631–640PubMedGoogle Scholar
  80. 80.
    Romani N, Koide S, Crowley M, Witmer-Pack M, Livingstone AM, Fathman CG, Inaba K, Steinman RM (1989) Presentation of exogenous protein antigens by dendritic cells to T cell clones: intact protein is presented best by immature, epidermal Langerhans cells. J Exp Med 169:1169–1178PubMedGoogle Scholar
  81. 81.
    Pure E, Inaba K, Crowley MT, Tardelli L, Witmer-Pack MD, Ruberti G, Fathman G, Steinman RM (1990) Antigen processing by epidermal Langerhans cells correlates with the level of biosynthesis of major histocompatibility complex class II molecules and expression of invariant chain. J Exp Med 172:1459–1469PubMedGoogle Scholar
  82. 82.
    Figdor CG, van Kooyk Y, Adema GJ (2002) C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol 2:77–84PubMedGoogle Scholar
  83. 83.
    Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295:1898–1901PubMedGoogle Scholar
  84. 84.
    Kalergis AM, Ravetch JV (2002) Inducing tumor immunity through the selective engagement of activating Fcγ receptors on dendritic cells. J Exp Med 195:1653–1659PubMedGoogle Scholar
  85. 85.
    Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bonvini E, Koenig S, Steinman RM, Ravetch JV, Dhodapkar MV (2005) Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci USA 102:2910–2915PubMedGoogle Scholar
  86. 86.
    Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and toll-like receptor 2. J Exp Med 197:1107–1117PubMedGoogle Scholar
  87. 87.
    Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effects of β-glucans. J Exp Med 197:1119–1124PubMedGoogle Scholar
  88. 88.
    Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis ESC (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22:507–517PubMedGoogle Scholar
  89. 89.
    Mahnke K, Guo M, Lee S, Sepulveda H, Swain SL, Nussenzweig M, Steinman RM (2000) The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation viamajor histocompatibility complex class II-positive lysosomal compartments. J Cell Biol 151:673–683PubMedGoogle Scholar
  90. 90.
    Jung S, Unutmaz D, Wong P, Sano GI, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, Pamer EG, Littman DR, Lang RA (2002) In vivo depletion of CD11c+ dendritic cells abrogation priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17:211–220PubMedGoogle Scholar
  91. 91.
    Belz GT, Behrens GM, Smith CM, Miller JF, Jones C, Lejon K, Fathman CG, Mueller SN, Shortman K, Carbone FR, Heath WR (2002) The CD8α+ dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med 196:1099–1104PubMedGoogle Scholar
  92. 92.
    Liu K, Iyoda T, Saternus M, Kimura K, Inaba K, Steinman RM (2002) Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 196:1091–1097PubMedGoogle Scholar
  93. 93.
    Houde M, Bertholet S, Gagnon E, Brunet S, Goyette G, Laplante A, Princiotta MF, Thibault P, Sacks D, Desjardins M (2003) Phagosomes are competent organelles for antigen cross-presentation. Nature 425:402–406PubMedGoogle Scholar
  94. 94.
    Guermonprez P, Saveanu L, Kleijmeer M, Davoust J, Van Endert P, Amigorena S (2003) ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425:397–402PubMedGoogle Scholar
  95. 95.
    Touret N, Paroutis P, Terebiznik M, Harrison R, Trombetta S, Pypaert M, Chow A, Jiang A, Shaw J, Yip C, Moore HP, Van Der Wel N, Houben D, Peters PJ, de Chastellier C, Mellman I, Grinstein S (2005) Quantitative and dynamic assessment of the contribution of the endoplasmic reticulum to phagosome formation. Cell 123:157–170PubMedGoogle Scholar
  96. 96.
    Lizee G, Basha G, Tiong J, Julien JP, Tian M, Biron KE, Jefferies WA (2003) Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain. Nat Immunol 4:1065–1073PubMedGoogle Scholar
  97. 97.
    den Haan J, Lehar S, Bevan M (2000) CD8+ but not CD8− dendritic cells crossprime cytotoxic T cells in vivo. J Exp Med 192:1685–1696Google Scholar
  98. 98.
    Wilson NS, El-Sukkari D, Villadangos JA (2004) Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood 103:2187–2195PubMedGoogle Scholar
  99. 99.
    Trombetta ES, Mellman I (2005) Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol 23:975–1028PubMedGoogle Scholar
  100. 100.
    Garrett WS, Chen LM, Kroschewski R, Ebersold M, Turley S, Trombetta S, Galan JE, Mellman I (2000) Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102:325–334PubMedGoogle Scholar
  101. 101.
    Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I (2003) Activation of lysosomal function during dendritic cell maturation. Science 299:1400–1403PubMedGoogle Scholar
  102. 102.
    Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307:1630–1634PubMedGoogle Scholar
  103. 103.
    Turley SJ, Inaba K, Garrett WS, Ebersold M, Untermaehrer J, Steinman RM, Mellman I (2000) Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288:522–527PubMedGoogle Scholar
  104. 104.
    Chow A, Toomre D, Garrett W, Mellman I (2002) Dendritic cellmaturation triggers retrograde transport of MHC class II transport from lysosomes to the plasma membrane. Nature 418:988–994PubMedGoogle Scholar
  105. 105.
    Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C (2005) Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887–892PubMedGoogle Scholar
  106. 106.
    Platt N, Suzuki H, Kurihara Y, Kodama T, Gordon S (1996) Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc Natl Acad Sci USA 93:12456–12460PubMedGoogle Scholar
  107. 107.
    Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90PubMedGoogle Scholar
  108. 108.
    Mevorach D, Mascarenhas JO, Gershov D, Elkon KB (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188:2313–2320PubMedGoogle Scholar
  109. 109.
    Savill JS, Dransfield I, Hogg N, Haslett C (1990) Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343:170–173PubMedGoogle Scholar
  110. 110.
    Ogden CA, de Cathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, Henson PM (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194:781–796PubMedGoogle Scholar
  111. 111.
    Devitt A, Moffatt OD, Raykundalia C, Capra JD, Simmons DL, Gregory CD (1998) Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392:505–509PubMedGoogle Scholar
  112. 112.
    Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells Invivo. J Exp Med 192:359–366PubMedGoogle Scholar
  113. 113.
    Norsworthy PJ, Fossati-Jimack L, Cortes-Hernandez J, Taylor PR, Bygrave AE, Thompson RD, Nourshargh S, Walport MJ, Botto M (2004) Murine CD93 (C1qRp) contributes to the removal of apoptotic cells in vivo but is not required for C1qmediated enhancement of phagocytosis. J Immunol 172:3406–3414PubMedGoogle Scholar
  114. 114.
    Fadok VA, Warner ML, Bratton DL, Henson PM (1998) CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (αvβ3). J Immunol 161:6250–6257PubMedGoogle Scholar
  115. 115.
    Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, Earp HS, Matsushima GK (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411:207–211PubMedGoogle Scholar
  116. 116.
    Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA (2003) Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302:1560–1563PubMedGoogle Scholar
  117. 117.
    Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150PubMedGoogle Scholar
  118. 118.
    Rubartelli A, Poggi A, Zocchi MR (1997) The selective engulfment of apoptotic bodies by dendritic cells is mediated by the αvβ3 integrin and requires intracellular and extracellular calcium. Eur J Immunol 27:1893–1900PubMedGoogle Scholar
  119. 119.
    Albert ML, Pearce SFA, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N (1998) Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188:1359–1368PubMedGoogle Scholar
  120. 120.
    Verbovetski I, Bychkov H, Trahtemberg U, Shapira I, Hareuveni M, Ben-Tal O, Kutikov I, Gil O, Mevorach D (2002) Opsonization of apoptotic cells by autologous iC3b facilities clearance by immature dendritic cells, down-regulates DR and CD86, and up-regulates CC chemokine receptor 7. J Exp Med 196:1553–1561PubMedGoogle Scholar
  121. 121.
    Miyasaka K, Hanayama R, Tanaka M, Nagata S (2004) Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol 34:1414–1422PubMedGoogle Scholar
  122. 122.
    Nauta AJ, Castellano G, Xu W, Woltman AM, Borrias MC, Daha MR, van Kooten C, Roos A (2004) Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J Immunol 173:3044–3050PubMedGoogle Scholar
  123. 123.
    Belz GT, Vremec D, Febbraio M, Corcoran L, Shortman K, Carbone FR, Heath WR (2002) CD36 is differentially expressed by CD8+ splenic dendritic cells but is not required for cross-presentation in vivo. J Immunol 168:6066–6070PubMedGoogle Scholar
  124. 124.
    Schulz O, Pennington DJ, Hodivala-Dilke K, Febbraio M, Reis E Sousa C (2002) CD36 or αvβ3 and αvβ5 integrins are not essential for MHC class I cross-presentation of cell-associated antigen by CD8α+ murine dendritic cells. J Immunol 168:6057–6065PubMedGoogle Scholar
  125. 125.
    Henri S, Vremec D, Kamath A, Waithman J, Williams S, Benoist C, Burnham K, Saeland S, Handman E, Shortman K (2001) The dendritic cell populations of mouse lymph nodes. J Immunol 167:741–748PubMedGoogle Scholar
  126. 126.
    Park CG, Takahara K, Umemoto E, Yashima Y, Matsubara K, Matsuda Y, Clausen BE, Inaba K, Steinman RM (2001) Five mouse homologues of the human dendritic cell C-type lectin, DC-SIGN. Int Immunol 13:1283–1290PubMedGoogle Scholar
  127. 127.
    Briken V, Jackman RM, Watts GF, Rogers RA, Porcelli SA (2000) Human CD1b and CD1c isoforms survey different intracellular compartments for the presentation of microbial lipid antigens. J Exp Med 192:281–288PubMedGoogle Scholar
  128. 128.
    Cao X, Sugita M, Van Der Wel N, Lai J, Rogers RA, Peters PJ, Brenner MB (2002) CD1 molecules efficiently present antigen in immature dendritic cells and traffic independently of MHC class II during dendritic cell maturation. J Immunol 169:4770–4777PubMedGoogle Scholar
  129. 129.
    Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–1789PubMedGoogle Scholar
  130. 130.
    Mattner J, Debord KL, Ismail N, Goff RD, Cantu C, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529PubMedGoogle Scholar
  131. 131.
    Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520–525PubMedGoogle Scholar
  132. 132.
    Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCRmediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626–1629PubMedGoogle Scholar
  133. 133.
    Schmieg J, Yang G, Franck RW, Tsuji M (2003) Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand α-galactosylceramide. J Exp Med 198:1631–1641PubMedGoogle Scholar
  134. 134.
    Wu D, Xing GW, Poles MA, Horowitz A, Kinjo Y, Sullivan B, Bodmer-Narkevitch V, Plettenburg O, Kronenberg M, Tsuji M, Ho DD, Wong CH (2005) Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. Proc Natl Acad Sci USA 102:1351–1356PubMedGoogle Scholar
  135. 135.
    Kojo S, Seino K, Harada M, Watarai H, Wakao H, Uchida T, Nakayama T, Taniguchi M (2005) Induction of regulatory properties in dendritic cells by Vα14 NKT cells. J Immunol 175:3648–3655PubMedGoogle Scholar
  136. 136.
    Trumpfheller C, Finke JS, Lopez CB, Moran TM, Moltedo B, Soares H, Huang Y, Schlesinger SJ, Park CG, Nussenzweig MC, Granelli-Piperno A, Steinman RM (2006) Intensified and protective CD4+ T cell immunity at amucosal surface after a single dose of anti-dendritic cell HIV gag fusion antibody vaccine. J Exp Med 203:607–617PubMedGoogle Scholar
  137. 137.
    Probst HC, Lagnel J, Kollias G, van den Broek M (2003) Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 18:713–720PubMedGoogle Scholar
  138. 138.
    Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6:280–286PubMedGoogle Scholar
  139. 139.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedGoogle Scholar
  140. 140.
    Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM (2004) The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 199:1607–1618PubMedGoogle Scholar
  141. 141.
    Inaba K, Witmer-Pack M, Inaba M, Hathcock KS, Sakuta H, Azuma M, Yagita H, Okumura K, Linsley PS, Ikehara S, Muramatsu S, Hodes RJ, Steinman RM (1994) The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med 180:1849–1860PubMedGoogle Scholar
  142. 142.
    Caux C, Vanbervliet B, Massacrier C, Azuma M, Okumura K, Lanier LL, Banchereau J (1994) B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells. J Exp Med 180:1841–1847PubMedGoogle Scholar
  143. 143.
    Sporri R, Reis e Sousa C (2005) Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol 6:163–170PubMedGoogle Scholar
  144. 144.
    Flores-Romo L, Bjorck P, Duvert V, Van Kooten C, Saeland S, Banchereau J (1997) CD40 ligation on human CD34+ hematopoietic progenitors induces their proliferation and differentiation into functional dendritic cells. J Exp Med 185:341–349PubMedGoogle Scholar
  145. 145.
    Moodycliffe AM, Shreedhar V, Ullrich SE, Walterscheid J, Bucana C, Kripke ML, Flores-Romo L (2000) CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes. J Exp Med 191:2011–2020PubMedGoogle Scholar
  146. 146.
    Josien R, Hi HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y (2000) TRANCE, a tumor necrosis familymember, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 191:495–501PubMedGoogle Scholar
  147. 147.
    Delamarre L, Holcombe H, Mellman I (2003) Presentation of exogenous antigens onmajor histocompatibility complex(MHC) class I and MHC class II molecules is differentially regulated during dendritic cell maturation. J Exp Med 198:111–122PubMedGoogle Scholar
  148. 148.
    Schulz O, Edwards AD, Schito M, Aliberti J, Manickasingham S, Sher A, Reis e Sousa C (2000) CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13:453–462PubMedGoogle Scholar
  149. 149.
    Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117:515–526PubMedGoogle Scholar
  150. 150.
    Moser M, Murphy KM (2000) Dendritic cell regulation of Th1-Th2 development. Nat Immunol 1:199–205PubMedGoogle Scholar
  151. 151.
    Le Bon A, Schiavoni G, D’Agostinio G, Gresser I, Belardelli F, Tough DF (2001) Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14:461–470PubMedGoogle Scholar
  152. 152.
    Proietti E, Bracci L, Puzelli S, Di Pucchio T, Sestili P, De Vincenzi E, Venditti M, Capone I, Seif I, De Maeyer E, Tough D, Donatelli I, Belardelli F (2002) Type I IFN as a natural adjuvant for a protective immune response: lessons from the influenza vaccine model. J Immunol 169:375–383PubMedGoogle Scholar
  153. 153.
    Le Bon A, Etchart N, Rossmann C, Ashton M, Hou S, Gewert D, Borrow P, Tough DF (2003) Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 4:1009–1015PubMedGoogle Scholar
  154. 154.
    Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036PubMedGoogle Scholar
  155. 155.
    Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG (2003) TNF/iNOS-producing dendritic cellsmediate innate immune defense against bacterial infection. Immunity 19:59–70PubMedGoogle Scholar
  156. 156.
    Lowes MA, Chamian F, Abello MV, Lin SL, Nussbaum R, Novitskaya I, Carbonaro H, Cardinale I, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Wittkowski KM, Papp K, Garovoy M, Dummer W, Steinman RM, Krueger JG (2005) Increase in TNF-and iNOS-producing dendritic cells in psoriasis and reduction with anti-CD11a. Proc Natl Acad Sci USA 102:19057–19062PubMedGoogle Scholar
  157. 157.
    Kumanogoh A, Shikina T, Suzuki K, Uematsu S, Yukawa K, Kashiwamura S, Tsutsui H, Yamamoto M, Takamatsu H, Ko-Mitamura EP, Takegahara N, Marukawa S, Ishida I, Morishita H, Prasad DV, Tamura M, Mizui M, Toyofuku T, Akira S, Takeda K, Okabe M, Kikutani H (2005) Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22:305–316PubMedGoogle Scholar
  158. 158.
    Marsland BJ, Battig P, Bauer M, Ruedl C, Lassing U, Beerli RR, Dietmeier K, Ivanova L, Pfister T, Vogt L, Nakano H, Nembrini C, Saudan P, Kopf M, Bachmann MF (2005) CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 22:493–505PubMedGoogle Scholar
  159. 159.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedGoogle Scholar
  160. 160.
    Lugo-Villarino G, Maldonado-Lopez R, Possemato R, Penaranda C, Glimcher LH (2003) T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells. Proc Natl Acad Sci USA 100:7749–7754PubMedGoogle Scholar
  161. 161.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680PubMedGoogle Scholar
  162. 162.
    MacDonald AS, Straw AD, Dalton NM, Pearce EJ (2002) Th2 response induction by dendritic cells: a role for CD40. J Immunol 168:537–540PubMedGoogle Scholar
  163. 163.
    Cervi L, MacDonald AS, Kane C, Dzierszinski F, Pearce EJ (2004) Dendritic cells copulsed with microbial and helminth antigens undergo modified maturation, segregate the antigens to distinct intracellular compartments, and concurrently induce microbe-specific Th1 and helminth-specific Th2 responses. J Immunol Methods 172:2016–2020Google Scholar
  164. 164.
    Traidl-Hoffmann C, Mariani V, Hochrein H, Karg K, Wagner H, Ring J, Mueller MJ, Jakob T, Behrendt H (2005) Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization. J Exp Med 201:627–636PubMedGoogle Scholar
  165. 165.
    Agea E, Russano A, Bistoni O, Mannucci R, Nicoletti I, Corazzi L, Postle AD, De Libero G, Porcelli SA, Spinozzi F (2005) Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med 202:295–308PubMedGoogle Scholar
  166. 166.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376PubMedGoogle Scholar
  167. 167.
    Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14PubMedGoogle Scholar
  168. 168.
    Gilliet M, Boonstra A, Paturel C, Antonenko S, Xu XL, Trinchieri G, O’Garra A, Liu YJ (2002) The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colonystimulating factor. J Exp Med 195:953–958PubMedGoogle Scholar
  169. 169.
    Naik SH, Proietto AI, Wilson NS, Dakic A, Schnorrer P, Fuchsberger M, Lahoud MH, O’Keeffe M, Shao QX, Chen WF, Villadangos JA, Shortman K, Wu L (2005) Generation of splenic CD8+ and CD8− dendritic cell equivalents in Fmslike tyrosine kinase 3 ligand bone marrow cultures. J Immunol 174:6592–6597PubMedGoogle Scholar
  170. 170.
    Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, Steinman RM (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen processing dendritic cells. J Exp Med 198:235–247PubMedGoogle Scholar
  171. 171.
    Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM (2004) CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477PubMedGoogle Scholar
  172. 172.
    Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249PubMedGoogle Scholar
  173. 173.
    Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–777PubMedGoogle Scholar
  174. 174.
    Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K (2005) Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202:637–650PubMedGoogle Scholar
  175. 175.
    Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737PubMedGoogle Scholar
  176. 176.
    Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28PubMedGoogle Scholar
  177. 177.
    Krieg AM (2003) CpG motifs: the active ingredient in bacterial extracts? Nat Med 9:831–835PubMedGoogle Scholar
  178. 178.
    Vasilakos JP, Smith RM, Gibson SJ, Lindh JM, Pederson LK, Reiter MJ, Smith MH, Tomai MA (2000) Adjuvant activities of immune response modifier R-848: comparison with CpG ODN. Cell Immunol 204:64–74PubMedGoogle Scholar
  179. 179.
    Mazzoni A, Segal DM (2004) Controlling the Toll road to dendritic cell polarization. J Leukoc Biol 75:721–730PubMedGoogle Scholar
  180. 180.
    Didierlaurent A, Ferrero I, Otten LA, Dubois B, Reinhardt M, Carlsen H, Blomhoff R, Akira S, Kraehenbuhl JP, Sirard JC (2004) Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response. J Immunol 172:6922–6930PubMedGoogle Scholar
  181. 181.
    Redecke V, Hacker H, Datta SK, Fermin A, Pitha PM, Broide DH, Raz E (2004) Activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739–2743PubMedGoogle Scholar
  182. 182.
    Kobayashi T, Yoshimura A (2005) Keeping DCs awake by putting SOCS1 to sleep. Trends Immunol 26:177–179PubMedGoogle Scholar
  183. 183.
    Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptormediated immune responses. Nat Rev Immunol 5:446–458PubMedGoogle Scholar
  184. 184.
    Armant M, Avice MN, Hermann P, Rubio M, Kiniwa M, Delespesse G, Sarfati M (1999) CD47 ligation selectively downregulates human interleukin 12 production. J Exp Med 190:1175–1182PubMedGoogle Scholar
  185. 185.
    Demeure CE, Tanaka H, Mateo V, Rubio M, Delespesse G, Sarfati M (2000) CD47 engagement inhibits cytokine production and maturation of human dendritic cells. J Immunol 164:2193–2199PubMedGoogle Scholar
  186. 186.
    Hochrein H, O’Keeffe M, Luft T, Vandenabeele S, Grumont RJ, Maraskovsky E, Shortman K (2000) Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med 192:823–834PubMedGoogle Scholar
  187. 187.
    Yao Y, Li W, Kaplan MH, Chang CH (2005) Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells. J Exp Med 201:1899–1903PubMedGoogle Scholar
  188. 188.
    Rotta G, Edwards EW, Sangaletti S, Bennett C, Ronzoni S, Colombo MP, Steinman RM, Randolph GJ, Rescigno M (2003) Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo. J Exp Med 198:1253–1263PubMedGoogle Scholar
  189. 189.
    Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG (2005) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105:1162–1169PubMedGoogle Scholar
  190. 190.
    Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196:459–468PubMedGoogle Scholar
  191. 191.
    Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196:447–457PubMedGoogle Scholar
  192. 192.
    Grohmann U, Fallarino F, Bianchi R, Orabona C, Vacca C, Fioretti MC, Puccetti P (2003) A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J Exp Med 198:153–160PubMedGoogle Scholar
  193. 193.
    Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S (1993) Natural killer cell stimulatory factor [interleukin 12 (IL-12)] induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 177:1199–1204PubMedGoogle Scholar
  194. 194.
    Nathan CF, Murray HW, Wiebe ME, Rubin BY (1983) Identification of interferongamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 158:670–689PubMedGoogle Scholar
  195. 195.
    Schreiber RD, Hicks LJ, Celada A, Buchmeier NA, Gray PW (1985) Monoclonal antibodies to murine γ-interferon which differentially modulate macrophage activation and antiviral activity. J Immunol 134:1609PubMedGoogle Scholar
  196. 196.
    Granelli-Piperno A, Pope M, Inaba K, Steinman RM (1995) Coexpression of NF-kB/Regl and Sp1 transcription factors in human immunodeficiency virus 1-induced, dendritic cell-T-cell syncytia. Proc Natl Acad Sci USA 92:10944–10948PubMedGoogle Scholar
  197. 197.
    Lazarski CA, Chaves FA, Jenks SA, Wu S, Richards KA, Weaver JM, Sant AJ (2005) The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance. Immunity 23:29–40PubMedGoogle Scholar
  198. 198.
    Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J, Ahmed R (1999) Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 286:1377–1381PubMedGoogle Scholar
  199. 199.
    Swain SL, Hu H, Huston G (1999) Class II-independent generation of CD4 memory T cells from effectors. Science 286:1381–1383PubMedGoogle Scholar
  200. 200.
    Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2:251–262PubMedGoogle Scholar
  201. 201.
    Boscardin SB, Hafalla JC, Silva A, Masilamani RF, Zebroski H, Zavala F, Steinman RM, Nussenzweig RS, Nussenzweig MC (2006) Antigen targeting to dendritic cells elicits improved and long-lived T cell help for antibody responses. J Exp Med 203:599–606PubMedGoogle Scholar
  202. 202.
    Balazs M, Martin F, Zhou T, Kearney JF (2002) Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 17:341–352PubMedGoogle Scholar
  203. 203.
    Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303:1662–1665PubMedGoogle Scholar
  204. 204.
    Fayette J, Dubois B, Vandenabelle S, Bridon JM, Vanbervliet B, Durand I, Banchereau J, Caux C, Briere F (1997) Human dendritic cells skew isotype switching of CD40-activated naive B cells towards IgA1 and IgA2. J Exp Med 185:1909–1918PubMedGoogle Scholar
  205. 205.
    Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829PubMedGoogle Scholar
  206. 206.
    Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99:351–358PubMedGoogle Scholar
  207. 207.
    Hawiger D, Masilamani RF, Bettelli E, Kuchroo VK, Nussenzweig MC (2004) Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity 20:695–705PubMedGoogle Scholar
  208. 208.
    Ebner S, Ehammer Z, Holzmann S, Schwingshackl P, Forstner M, Stoitzner P, Huemer GM, Fritsch P, Romani N (2004) Expression of C-type lectin receptors by subsets of dendritic cells in human skin. Int Immunol 16:877–887PubMedGoogle Scholar
  209. 209.
    Yoneyama H, Matsuno K, Toda E, Nishiwaki T, Matsuo N, Nakano A, Narumi S, Lu B, Gerard C, Ishikawa S, Matsushima K (2005) Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs. J Exp Med 202:425–435PubMedGoogle Scholar
  210. 210.
    Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H, Brimnes MK, Moltedo B, Moran TM, Steinman RM (2004) In vivo targeting of antigens to the DEC-205 receptor on maturing dendritic cells improves T cell vaccination. J Exp Med 199:815–824PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • R. M. Steinman
    • 1
  • H. Hemmi
    • 1
  1. 1.Laboratory of Cellular Physiology and ImmunologyThe Rockefeller UniversityNew YorkUSA

Personalised recommendations