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Tissue-based class control: the other side of tolerance

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Abstract

In this Essay, we offer a new perspective on how immune responses are regulated. We do not cover how they are turned on and off, but focus instead on the second major aspect of an immune response: the control of effector class. Although it is generally thought that the class of an immune response is tailored to fit the invading pathogen, we suggest here that it is primarily tailored to fit the tissue in which the response occurs. To this end, we cover such topics as the nature of T helper (TH) cell subsets (current and yet to be discovered), the nature of privileged sites, the difference between oral tolerance and oral vaccination, why the route of immunization matters, whether the TH1-type response is really the immune system's primary defense, and whether there might be a different role for some regulatory T cells.

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Figure 1: A model for tissue-based class control of immune responses.

References

  1. Streilein, J. W. Pathologic lesions of GVH disease in hamsters: antigenic target versus 'innocent bystander'. Prog. Exp. Tumor Res. 16, 396–408 (1972).

    Article  CAS  PubMed  Google Scholar 

  2. Elson, C. O., Reilly, R. W. & Rosenberg, I. H. Small intestinal injury in the graft versus host reaction: an innocent bystander phenomenon. Gastroenterology 72, 886–889 (1977).

    CAS  PubMed  Google Scholar 

  3. Krook, H. et al. A distinct Th1 immune response precedes the described Th2 response in islet xenograft rejection. Diabetes 51, 79–86 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Knisely, T. L., Luckenbach, M. W., Fischer, B. J. & Niederkorn, J. Y. Destructive and nondestructive patterns of immune rejection of syngeneic intraocular tumors. J. Immunol. 138, 4515–4523 (1987).

    CAS  PubMed  Google Scholar 

  5. Abram, M. et al. Effects of pregnancy-associated Listeria monocytogenes infection: necrotizing hepatitis due to impaired maternal immune response and significantly increased abortion rate. Virchows Arch. 441, 368–379 (2002).

    Article  PubMed  Google Scholar 

  6. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nature Rev. Immunol. 4, 469–478 (2004).

    Article  CAS  Google Scholar 

  7. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).

    Article  CAS  Google Scholar 

  8. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dowling, D. J. et al. Major secretory antigens of the helminth Fasciola hepatica activate a suppressive dendritic cell phenotype that attenuates Th17 cells but fails to activate Th2 immune responses. Infect. Immun. 78, 793–801 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Koch, A. L. Bacterial wall as target for attack: past, present, and future research. Clin. Microbiol. Rev. 16, 673–687 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Andersen-Nissen, E. et al. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl Acad. Sci. USA 102, 9247–9252 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Matzinger, P. Friendly and dangerous signals: is the tissue in control? Nature Immunol. 8, 11–13 (2007).

    Article  CAS  Google Scholar 

  15. Kelso, A. Th1 and Th2 subsets: paradigms lost? Immunol. Today 16, 374–379 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pulendran, B. et al. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J. Immunol. 167, 5067–5076 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Yang, D. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2–MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 205, 79–90 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Prussin, C., Lee, J. & Foster, B. Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5+ and IL-5 TH2 responses. J. Allergy Clin. Immunol. 124, 1326–1332 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hume, D. M. & Egdahl, R. H. Progressive destruction of renal homografts isolated from the regional lymphatics of the host. Surgery 38, 194–214 (1955).

    CAS  PubMed  Google Scholar 

  21. Medawar, P. B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Barker, C. F. & Billingham, R. E. Immunologically privileged sites. Adv. Immunol. 25, 1–54 (1977).

    CAS  PubMed  Google Scholar 

  23. Barker, C. F. & Billingham, R. E. The lymphatic status of hamster cheek pouch tissue in relation to its properties as a graft and as a graft site. J. Exp. Med. 133, 620–639 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fijak, M. & Meinhardt, A. The testis in immune privilege. Immunol. Rev. 213, 66–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Ferguson, T. A. & Griffith, T. S. A vision of cell death: Fas ligand and immune privilege 10 years later. Immunol. Rev. 213, 228–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Caspi, R. R. Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006).

    Article  PubMed  Google Scholar 

  27. Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nature Rev. Immunol. 3, 879–889 (2003).

    Article  CAS  Google Scholar 

  28. Niederkorn, J. Y. & Stein-Streilein, J. History and physiology of immune privilege. Ocul. Immunol. Inflamm. 18, 19–23 (2010).

    Article  PubMed  Google Scholar 

  29. Coffman, R. L., Lebman, D. A. & Shrader, B. Transforming growth factor β specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J. Exp. Med. 170, 1039–1044 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Sonoda, E. et al. Transforming growth factor β induces IgA production and acts additively with interleukin 5 for IgA production. J. Exp. Med. 170, 1415–1420 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. Boirivant, M. et al. Vasoactive intestinal polypeptide modulates the in vitro immunoglobulin A production by intestinal lamina propria lymphocytes. Gastroenterology 106, 576–582 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Kimata, H. & Fujimoto, M. Vasoactive intestinal peptide specifically induces human IgA1 and IgA2 production. Eur. J. Immunol. 24, 2262–2265 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Fang, Y., Yu, S., Ellis, J. S., Sharav, T. & Braley-Mullen, H. Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. J. Leukoc. Biol. 87, 1019–1028 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shinohara, M. L., Kim, J. H., Garcia, V. A. & Cantor, H. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 29, 68–78 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khoury, S. J., Hancock, W. W. & Weiner, H. L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med. 176, 1355–1364 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Miller, A., Lider, O., Roberts, A. B., Sporn, M. B. & Weiner, H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor β after antigen-specific triggering. Proc. Natl Acad. Sci. USA 89, 421–425 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scadding, G. & Durham, S. Mechanisms of sublingual immunotherapy. J. Asthma 46, 322–334 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Salk, D. & Salk, J. Vaccinology of poliomyelitis. Vaccine 2, 59–74 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Sterner, R. T., Meltzer, M. I., Shwiff, S. A. & Slate, D. Tactics and economics of wildlife oral rabies vaccination, Canada and the United States. Emerg. Infect. Dis. 15, 1176–1184 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Chen, Y. et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 376, 177–180 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Alpan, O., Rudomen, G. & Matzinger, P. The role of dendritic cells, B cells, and M cells in gut-oriented immune responses. J. Immunol. 166, 4843–4852 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Mestecky, J., Russell, M. W. & Elson, C. O. Perspectives on mucosal vaccines: is mucosal tolerance a barrier? J. Immunol. 179, 5633–5638 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Maloy, K. J., Donachie, A. M., O'Hagan, D. T. & Mowat, A. M. Induction of mucosal and systemic immune responses by immunization with ovalbumin entrapped in poly(lactide-co-glycolide) microparticles. Immunology 81, 661–667 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Weiner, H. L. Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol. Rev. 182, 207–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev. Immunol. 10, 131–144 (2010).

    Article  CAS  Google Scholar 

  46. Kaplan, H. J. & Niederkorn, J. Y. Regional immunity and immune privilege. Chem. Immunol. Allergy 92, 11–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Boehm, U., Klamp, T., Groot, M. & Howard, J. C. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Tracey, K. J. & Cerami, A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491–503 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Kagi, D., Ledermann, B., Burki, K., Zinkernagel, R. M. & Hengartner, H. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu. Rev. Immunol. 14, 207–232 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Mukaida, N. Antibody-dependent cell-mediated cytotoxicity (ADCC). Nippon Rinsho 57 (Suppl.), 571–573 (1999).

    PubMed  Google Scholar 

  51. MacMicking, J., Xie, Q. W. & Nathan, C. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Carroll, M. C. The role of complement and complement receptors in induction and regulation of immunity. Annu. Rev. Immunol. 16, 545–568 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Chaouat, G. et al. TH1/TH2 paradigm in pregnancy: paradigm lost? Int. Arch. Allergy Immunol. 134, 93–119 (2004).

    Article  PubMed  Google Scholar 

  54. Linthicum, D. S., Mackay, I. R. & Carnegie, P. R. Measurement of cell-mediated inflammation in experimental murine autoimmune encephalomyelitis by radioisotopic labeling. J. Immunol. 123, 1799–1805 (1979).

    CAS  PubMed  Google Scholar 

  55. Gilliet, M. & Lande, R. Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr. Opin. Immunol. 20, 401–407 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Nijhuis, L. E., Olivier, B. J. & de Jonge, W. J. Neurogenic regulation of dendritic cells in the intestine. Biochem. Pharmacol. 80, 2002–2008 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Tokuyama, H. & Tokuyama, Y. Retinoids enhance IgA production by lipopolysaccharide-stimulated murine spleen cells. Cell. Immunol. 150, 353–363 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Baeke, F., Takiishi, T., Korf, H., Gysemans, C. & Mathieu, C. Vitamin D: modulator of the immune system. Curr. Opin. Pharmacol. 10, 482–496 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Wilbanks, G. A., Mammolenti, M. & Streilein, J. W. Studies on the induction of anterior chamber-associated immune deviation (ACAID) III. Induction of ACAID depends upon intraocular transforming growth factor-β. Eur. J. Immunol. 22, 165–173 (1992).

    Article  CAS  PubMed  Google Scholar 

  60. Kosiewicz, M. M., Alard, P. & Streilein, J. W. Alterations in cytokine production following intraocular injection of soluble protein antigen: impairment in IFN-γ and induction of TGF-β and IL-4 production. J. Immunol. 161, 5382–5390 (1998).

    CAS  PubMed  Google Scholar 

  61. Stavnezer, J. & Kang, J. The surprising discovery that TGFβ specifically induces the IgA class switch. J. Immunol. 182, 5–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Penna, G. et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J. Immunol. 178, 145–153 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Imai, T. et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Lemire, J. M. & Adams, J. S. 1,25-Dihydroxyvitamin D3 inhibits the passive transfer of cellular immunity by a myelin basic protein-specific T cell clone. J. Bone Miner. Res. 7, 171–177 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Cheroutre, H. & Lambolez, F. The thymus chapter in the life of gut-specific intra epithelial lymphocytes. Curr. Opin. Immunol. 20, 185–191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Hue, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377 (2004).

    Article  PubMed  Google Scholar 

  69. Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Jameson, J. & Havran, W. L. Skin γδ T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114–122 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994).

    CAS  PubMed  Google Scholar 

  72. Boismenu, R., Hobbs, M. V., Boullier, S. & Havran, W. L. Molecular and cellular biology of dendritic epidermal T cells. Semin. Immunol. 8, 323–331 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Braun, A., Wiebe, P., Pfeufer, A., Gessner, R. & Renz, H. Differential modulation of human immunoglobulin isotype production by the neuropeptides substance P, NKA and NKB. J. Neuroimmunol. 97, 43–50 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Dunzendorfer, S. & Wiedermann, C. J. Neuropeptides and the immune system: focus on dendritic cells. Crit. Rev. Immunol. 21, 523–557 (2001).

    CAS  PubMed  Google Scholar 

  75. Ho, W. Z., Lai, J. P., Zhu, X. H., Uvaydova, M. & Douglas, S. D. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J. Immunol. 159, 5654–5660 (1997).

    CAS  PubMed  Google Scholar 

  76. Lai, J. P., Douglas, S. D. & Ho, W. Z. Human lymphocytes express substance P and its receptor. J. Neuroimmunol. 86, 80–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Qian, B. F., Zhou, G. Q., Hammarstrom, M. L. & Danielsson, A. Both substance P and its receptor are expressed in mouse intestinal T lymphocytes. Neuroendocrinology 73, 358–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Shibata, M., Hisajima, T., Nakano, M., Goris, R. C. & Funakoshi, K. Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine. Brain Behav. Immun. 22, 158–166 (2008).

    Article  CAS  Google Scholar 

  79. Meek, B., Speijer, D., de Jong, P. T., de Smet, M. D. & Peek, R. The ocular humoral immune response in health and disease. Prog. Retin. Eye Res. 22, 391–415 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Lausch, R. N., Monteiro, C., Kleinschrodt, W. R. & Oakes, J. E. Superiority of antibody versus delayed hypersensitivity in clearance of HSV-1 from eye. Invest. Ophthalmol. Vis. Sci. 28, 565–570 (1987).

    CAS  Google Scholar 

  81. Everson, M. P. et al. Dendritic cells from different tissues induce production of different T cell cytokine profiles. J. Leukoc. Biol. 59, 494–498 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Bode, U. et al. Dendritic cell subsets in lymph nodes are characterized by the specific draining area and influence the phenotype and fate of primed T cells. Immunology 123, 480–490 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Iliev, I. D., Mileti, E., Matteoli, G., Chieppa, M. & Rescigno, M. Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2, 340–350 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunol. 6, 507–514 (2005).

    Article  CAS  Google Scholar 

  85. Xia, S. et al. Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance. Blood 112, 3175–3185 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zeuthen, L. H., Fink, L. N. & Frokiaer, H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-β. Immunology 123, 197–208 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kunkel, E. J. et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192, 761–768 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Iwasaki, A. & Kelsall, B. L. Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190, 229–239 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mora, J. R. et al. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–316 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Calzascia, T. et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 22, 175–184 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Alyanakian, M. A. et al. Diversity of regulatory CD4+ T cells controlling distinct organ-specific autoimmune diseases. Proc. Natl Acad. Sci. USA 100, 15806–15811 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Alpan, O., Bachelder, E., Isil, E., Arnheiter, H. & Matzinger, P. 'Educated' dendritic cells act as messengers from memory to naive T helper cells. Nature Immunol. 5, 615–622 (2004).

    Article  CAS  Google Scholar 

  93. De Smedt, T. et al. Antigen-specific T lymphocytes regulate lipopolysaccharide-induced apoptosis of dendritic cells in vivo. J. Immunol. 161, 4476–4479 (1998).

    CAS  PubMed  Google Scholar 

  94. Helft, J. et al. Antigen-specific T-T interactions regulate CD4 T-cell expansion. Blood 112, 1249–1258 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Yu, L., Wang, L. & Chen, S. Endogenous Toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 14, 2592–2603 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Eisenbarth, S. C. et al. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645–1651 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Belkaid, Y. The role of CD4+CD25+ regulatory T cells in Leishmania infection. Expert Opin. Biol. Ther. 3, 875–885 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Jankovic, D. et al. Conventional T-bet+Foxp3 Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shah, P. D., Gilbertson, S. M. & Rowley, D. A. Dendritic cells that have interacted with antigen are targets for natural killer cells. J. Exp. Med. 162, 625–636 (1985).

    Article  CAS  PubMed  Google Scholar 

  101. Sitkovsky, M. & Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nature Rev. Immunol. 5, 712–721 (2005).

    Article  CAS  Google Scholar 

  102. Pulendran, B., Palucka, K. & Banchereau, J. Sensing pathogens and tuning immune responses. Science 293, 253–256 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Takahashi, H. et al. Detection and comparison of viral antigens in measles and rubella rashes. Clin. Infect. Dis. 22, 36–39 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Isa, M. B. et al. Comparison of immunoglobulin G subclass profiles induced by measles virus in vaccinated and naturally infected individuals. Clin. Diagn. Lab. Immunol. 9, 693–697 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Gonzalez, R., Franco, M., Sarmiento, L., Romero, M. & Schael, I. P. Serum IgA levels induced by rotavirus natural infection, but not following immunization with the RRV-TV vaccine (Rotashield), correlate with protection. J. Med. Virol. 76, 608–612 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Liew, F. Y., Russell, S. M., Appleyard, G., Brand, C. M. & Beale, J. Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity. Eur. J. Immunol. 14, 350–356 (1984).

    Article  CAS  PubMed  Google Scholar 

  107. Mora, J. R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003).

    Article  CAS  Google Scholar 

  109. Brandtzaeg, P. Induction of secretory immunity and memory at mucosal surfaces. Vaccine 25, 5467–5484 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Amiri, P. et al. Anti-immunoglobulin E treatment decreases worm burden and egg production in Schistosoma mansoni-infected normal and interferon γ knockout mice. J. Exp. Med. 180, 43–51 (1994).

    Article  CAS  PubMed  Google Scholar 

  111. King, C. L., Malhotra, I. & Jia, X. Schistosoma mansoni: protective immunity in IL-4-deficient mice. Exp. Parasitol. 84, 245–252 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Hogarth, P. J., Folkard, S. G., Taylor, M. J. & Bianco, A. E. Accelerated clearance of Onchocerca microfilariae and resistance to reinfection in interleukin-4 gene knockout mice. Parasite Immunol. 17, 653–657 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Brito, C. F., Caldas, I. R., Coura Filho, P., Correa-Oliveira, R. & Oliveira, S. C. CD4+ T cells of schistosomiasis naturally resistant individuals living in an endemic area produce interferon-γ and tumour necrosis factor-α in response to the recombinant 14 kDa Schistosoma mansoni fatty acid-binding protein. Scand. J. Immunol. 51, 595–601 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Viana, I. R. et al. Interferon-γ production by peripheral blood mononuclear cells from residents of an area endemic for Schistosoma mansoni. Trans. R. Soc. Trop. Med. Hyg. 88, 466–470 (1994).

    Article  CAS  PubMed  Google Scholar 

  115. Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Terrazas, C. A., Terrazas, L. I. & Gomez-Garcia, L. Modulation of dendritic cell responses by parasites: a common strategy to survive. J. Biomed. Biotechnol. 2010, 357106 (2010).

    PubMed  PubMed Central  Google Scholar 

  117. Thorstenson, K. M. & Khoruts, A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J. Immunol. 167, 188–195 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, X., Izikson, L., Liu, L. & Weiner, H. L. Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J. Immunol. 167, 4245–4253 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Coombes, J. L. et al. 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. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sun, J. B., Raghavan, S., Sjoling, A., Lundin, S. & Holmgren, J. Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+CD25+ and Foxp3CD25 CD4+ regulatory T cells. J. Immunol. 177, 7634–7644 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  122. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Shevach, E. M. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Shevach, E. M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell–IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zarember, K. A. & Godowski, P. J. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J. Immunol. 168, 554–561 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Hammad, H. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nature Med. 15, 410–416 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Shearer, J. D., Richards, J. R., Mills, C. D. & Caldwell, M. D. Differential regulation of macrophage arginine metabolism: a proposed role in wound healing. Am. J. Physiol. 272, E181–E190 (1997).

    CAS  PubMed  Google Scholar 

  131. Kropf, P. et al. Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J. 19, 1000–1002 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Rogers, M. et al. Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival. PLoS Pathog. 5, e1000555 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Davis, J. M. & Ramakrishnan, L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136, 37–49 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ulrichs, T. & Kaufmann, S. H. New insights into the function of granulomas in human tuberculosis. J. Pathol. 208, 261–269 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Siciliano, N. A., Skinner, J. A. & Yuk, M. H. Bordetella bronchiseptica modulates macrophage phenotype leading to the inhibition of CD4+ T cell proliferation and the initiation of a Th17 immune response. J. Immunol. 177, 7131–7138 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Everts, B. et al. Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J. Exp. Med. 206, 1673–1680 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Steinfelder, S. et al. The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1). J. Exp. Med. 206, 1681–1690 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. van der Kleij, D. et al. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277, 48122–48129 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Bergman, M. P. et al. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J. Exp. Med. 200, 979–990 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Meade, R. et al. Transforming growth factor-beta 1 inhibits murine immediate and delayed type hypersensitivity. J. Immunol. 149, 521–528 (1992).

    CAS  PubMed  Google Scholar 

  141. Bommireddy, R. & Doetschman, T. TGFβ1 and Treg cells: alliance for tolerance. Trends Mol. Med. 13, 492–501 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Goetzl, E. J. et al. Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC2 receptor for vasoactive intestinal peptide. Proc. Natl Acad. Sci. USA 98, 13854–13859 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Delgado, M., Chorny, A., Gonzalez-Rey, E. & Ganea, D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J. Leukoc. Biol. 78, 1327–1338 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Taylor, A. W., Yee, D. G., Nishida, T. & Namba, K. Neuropeptide regulation of immunity. The immunosuppressive activity of alpha-melanocyte-stimulating hormone (α-MSH). Ann. NY Acad. Sci. 917, 239–247 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Taylor, A. W. Modulation of regulatory T cell immunity by the neuropeptide alpha-melanocyte stimulating hormone. Cell. Mol. Biol. 49, 143–149 (2003).

    CAS  PubMed  Google Scholar 

  146. Mazzucchelli, R. et al. Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP. Blood 112, 3283–3292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Wiedermann, U. et al. Vitamin A deficiency increases inflammatory responses. Scand. J. Immunol. 44, 578–584 (1996).

    Article  CAS  PubMed  Google Scholar 

  149. Cantorna, M. T., Nashold, F. E. & Hayes, C. E. Vitamin A deficiency results in a priming environment conducive for Th1 cell development. Eur. J. Immunol. 25, 1673–1679 (1995).

    Article  CAS  PubMed  Google Scholar 

  150. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Bendelac, T. Honjo, B. Jabri, Y. Rosenberg, F. Di Rosa, R. Schwartz, N. Singh, the 'ghosts' (K. Abdi, A. Perez-Diez, A. Morgun and N. Shulzhenko) and especially P. Chappert for commenting on the manuscript. T.K. would like to express special thanks to D. Usharauli for his encouragement and support during the preparation of this Essay. We apologize to the authors whose work we didn't cite owing to lack of space. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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Matzinger, P., Kamala, T. Tissue-based class control: the other side of tolerance. Nat Rev Immunol 11, 221–230 (2011). https://doi.org/10.1038/nri2940

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