A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage

An Erratum to this article was published on 01 March 2007

This article has been updated

Abstract

For over 35 years, immunologists have divided T-helper (TH) cells into functional subsets. T-helper type 1 (TH1) cells—long thought to mediate tissue damage—might be involved in the initiation of damage, but they do not sustain or play a decisive role in many commonly studied models of autoimmunity, allergy and microbial immunity. A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system. A pathway named TH17 is now credited for causing and sustaining tissue damage in these diverse situations. The TH1 pathway antagonizes the TH17 pathway in an intricate fashion. The evolution of our understanding of the TH17 pathway illuminates a shift in immunologists' perspectives regarding the basis of tissue damage, where for over 20 years the role of TH1 cells was considered paramount.

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Figure 1: T-helper cell differentiation and regulation.

Katie Ris

Figure 2

Katie Ris

Change history

  • 21 February 2007

    In the version of this article initially published, the labeling in Figure 1 is incorrect. Tregs should be shown as producing TGF-β, not IL-17. The error has been corrected in the HTML and PDF versions of the article.

Notes

  1. 1.

    NOTE: In the version of this article initially published, the labeling in Figure 1 is incorrect. Tregs should be shown as producing TGF-β, not IL-17. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Coffman, R.L. & Carty, J.A. T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. J. Immunol. 136, 949–954 (1986).

    CAS  PubMed  Google Scholar 

  2. 2

    Mosmann, T.R., Cherwinski, H., Bond, M.W., Giedlin, M.A. & Coffman, R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Coffman, R.L. Origins of the TH1-TH2 model: a personal perspective. Nat. Immunol. 7, 539–541 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Steinmetz, M. et al. A molecular map of the immune response region from the major histocompatibility complex of the mouse. Nature 300, 35–42 (1982).

    CAS  Article  Google Scholar 

  5. 5

    Klein, J. & Nagy, Z. Trouble in the J-land. Nature 300, 12–13 (1982).

    Article  Google Scholar 

  6. 6

    Hedrick, S.M., Cohen, D., Nielsen, E. & Davis, M. Isolation of cDNA clones encoding T-cell-specific membrane-associated proteins. Nature 308, 149–153 (1984).

    CAS  Article  Google Scholar 

  7. 7

    Yanagi, Y. et al. A human T-cell specific cDNA clone encodes a protein with extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984).

    CAS  Article  Google Scholar 

  8. 8

    Cher, D.J. & Mosmann, T.R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J. Immunol. 138, 3688–3694 (1987).

    CAS  PubMed  Google Scholar 

  9. 9

    Fiorentino, D.F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991).

    CAS  PubMed  Google Scholar 

  10. 10

    Steinman, L. Optic neuritis, a new variant of experimental encephalomyelitis, a durable model for all seasons, now in its seventieth year. J. Exp. Med. 197, 1065–1071 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Benacerraf, B. & McCluskey, R. Methods of immunologic injury to tissues. Annu. Rev. Microbiol. 17, 263–284 (1963).

    CAS  Article  Google Scholar 

  12. 12

    Waksman, B.H. Auto-immunization and the lesions of autoimmunity. Medicine (Baltimore) 41, 93–141 (1962).

    CAS  Article  Google Scholar 

  13. 13

    Paterson, P.Y. Transfer of allergic encephalomyelitis by means of lymph node cells. J. Exp. Med. 111, 119–136 (1960).

    CAS  Article  Google Scholar 

  14. 14

    Billiau, A. et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J. Immunol. 140, 1506–1510 (1988).

    CAS  PubMed  Google Scholar 

  15. 15

    Ferber, I.A. et al. Mice with a disrupted interferon-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).

    CAS  PubMed  Google Scholar 

  16. 16

    Voorthuis, J.A. et al. Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-gamma in Lewis rats. Clin. Exp. Immunol. 81, 183–188 (1990).

    CAS  Article  Google Scholar 

  17. 17

    Willenborg, D., Fordham, S., Bernard, C.C., Cowden, W. & Ramshaw, I. IFN-γ plays a critical down-regulatory role in the induction and effector phase of MOG-induced encephalomyelitis. J. Immunol. 157, 3223–3227 (1996).

    CAS  PubMed  Google Scholar 

  18. 18

    Krakowski, M. & Owens, T. Interferon-γ confers resistance to EAE. Eur. J. Immunol. 26, 1641–1646 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Jacob, C.O., Holoshitz, J., Van der Meide, P., Strober, S. & McDevitt, H.O. Heterogeneous effects of IFN-γ in adjuvant arthritis. J. Immunol. 142, 1500–1505 (1989).

    CAS  PubMed  Google Scholar 

  20. 20

    Nakajima, H., Takamori, H., Hiyama, Y. & Tsukada, W. The effect of treatment with recombinant gamma-interferon on adjuvant-induced arthritis in rats. Agents Actions 34, 63–65 (1991).

    CAS  Article  Google Scholar 

  21. 21

    Zamvil, S. et al. T cell clones specific for myelin basic protein induce chronic relapsing EAE and demyelination. Nature 317, 355–358 (1985).

    CAS  Article  Google Scholar 

  22. 22

    Powell, M.B. et al. Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein specific T cell clones correlates with encephalitogenicity. Int. Immunol. 2, 539–544 (1990).

    CAS  Article  Google Scholar 

  23. 23

    Ando, D.G., Clayton, J., Kono, D., Urban, J.L. & Sercarz, E.E. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell. Immunol. 124, 132–143 (1989).

    CAS  Article  Google Scholar 

  24. 24

    Liu, J. et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat. Med. 4, 78–83 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Panitch, H.S., Hirsch, R.L., Schindler, J. & Johnson, K.P. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37, 1097–1102 (1987).

    CAS  Article  Google Scholar 

  26. 26

    Feldmann, M. & Steinman, L. Design of effective immunotherapy for human autoimmunity. Nature 435, 612–619 (2005).

    CAS  Article  Google Scholar 

  27. 27

    van Oosten, B.W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Kuhn, T.S. The Structure of Scientific Revolutions. (Univ. Chicago Press, Chicago, 1962).

    Google Scholar 

  29. 29

    Williams, R. Bone destruction by TH17. J. Exp. Med. 203, 2567 (2006).

    Article  Google Scholar 

  30. 30

    Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Tato, C.M. & O'Shea, J. What does it mean to be just 17? Nature 441, 166–168 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Gijbels, K., Brocke, S., Abrams, J. & Steinman, L. Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Mol. Med. 1, 795–805 (1995).

    CAS  Article  Google Scholar 

  39. 39

    Samoilova, E.B., Horton, J.L., Hilliard, B., Liu, T.S. & Chen, Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161, 6480–6486 (1998).

    CAS  PubMed  Google Scholar 

  40. 40

    Okuda, Y., Sakoda, S., Saeki, Y., Kishimoto, T. & Yanagihara, T. Enhancement of Th2 response in IL-6-deficient mice immunized with myelin oligodendrocyte glycoprotein. J. Neuroimmunol. 105, 120–123 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Di Marco, R. et al. Curative effects of recombinant human interleukin-6 in DA rats with protracted relapsing experimental allergic encephalomyelitis. J. Neuroimmunol. 116, 168–177 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Chen, Q. et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat. Immunol. 7, 1299–1308 (2006).

    CAS  Article  Google Scholar 

  44. 44

    Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).

    CAS  Article  Google Scholar 

  46. 46

    Steinman, L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat. Rev. Drug Discov. 4, 510–519 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Yang, X.D., Karin, N., Tisch, R., Steinman, L. & McDevitt, H.O. Inhibition of insulitis and prevention of diabetes in NOD mice by blocking L-selectin and VLA-4 adhesion receptors. Proc. Natl. Acad. Sci. USA 90, 10494–10498 (1993).

    CAS  Article  Google Scholar 

  48. 48

    Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Hellings, P.W. et al. Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am. J. Respir. Cell Mol. Biol. 28, 42–50 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Chen, Y. et al. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J. Biol. Chem. 278, 17036–17043 (2003).

    CAS  Article  Google Scholar 

  51. 51

    Rangachari, M. et al. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J. Exp. Med. 203, 2009–2019 (2006).

    CAS  Article  Google Scholar 

  52. 52

    Ivanov, I.I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  Article  Google Scholar 

  53. 53

    Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).

    CAS  Article  Google Scholar 

  54. 54

    Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

    CAS  Article  Google Scholar 

  55. 55

    Mangan, P.R. et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  Google Scholar 

  56. 56

    Ye, P. et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am. J. Respir. Cell Mol. Biol. 25, 335–340 (2001).

    CAS  Article  Google Scholar 

  57. 57

    Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    CAS  Article  Google Scholar 

  58. 58

    Schnyder-Candrian, S., et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).

    CAS  Article  Google Scholar 

  59. 59

    Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    CAS  Article  Google Scholar 

  60. 60

    Matusevicius, D. et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101–104 (1999).

    CAS  Article  Google Scholar 

  61. 61

    Albanesi, C. et al. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J. Invest. Dermatol. 115, 81–87 (2000).

    CAS  Article  Google Scholar 

  62. 62

    Albanesi, C., Cavani, A. & Girolomoni, G. IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. J. Immunol. 162, 494–502 (1999).

    CAS  PubMed  Google Scholar 

  63. 63

    Aarvak, T., Chabaud, M., Miossec, P. & Natvig, J.B. IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J. Immunol. 162, 1246–1251 (1999).

    CAS  Google Scholar 

  64. 64

    Infante-Duarte, C., Horton, H.F., Byrne, M.C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in Th cells. J. Immunol. 165, 6107–6115 (2000).

    CAS  Article  Google Scholar 

  65. 65

    Duerr, R., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  Article  Google Scholar 

  66. 66

    Sutton, C., Brereton, C., Keogh, B., Mills, K.H. & Lavelle, E.C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med. 203, 1685–1691 (2006).

    CAS  Article  Google Scholar 

  67. 67

    Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 7, 929–936 (2006).

    CAS  Article  Google Scholar 

  68. 68

    Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    CAS  Article  Google Scholar 

  69. 69

    Vollmer, T., Waldor, M.K., Steinman, L. & Conley, F. Depletion of T4-+ lymphocytes reactivates toxoplasmosis in the central nervous system. J. Immunol. 138, 3737–3741 (1987).

    CAS  PubMed  Google Scholar 

  70. 70

    Cantor, H., Simpson, E., Sato, V.L., Fathman, C.G. & Herzenberg, L.A. Characterization of subpopulations of T lymphocytes. I. Separation and functional studies of peripheral T-cells binding different amounts of fluorescent anti-Thy 1.2 (theta) antibody using a fluorescence-activated cell sorter (FACS). Cell. Immunol. 15, 180–196 (1975).

    CAS  Article  Google Scholar 

  71. 71

    Cantor, H. & Boyse, E.A. Functional subclasses of T-lymphocytes bearing different Ly antigens. I. The generation of functionally distinct T-cell subclasses is a differentiative process independent of antigen. J. Exp. Med. 141, 1376–1389 (1975).

    CAS  Article  Google Scholar 

  72. 72

    Fong, A. & Mosmann, T. The role of interferon-γ in delayed-type hypersensitivity mediated by TH1 clones. J. Immunol. 147, 2887–2893 (1989).

    Google Scholar 

  73. 73

    Lotze, M.T. & Tracey, K. High-mobility group box protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331–342 (2005).

    CAS  Article  Google Scholar 

  74. 74

    Shinohara, M.L. et al. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc. Natl. Acad. Sci. USA 102, 17101–17106 (2005).

    CAS  Article  Google Scholar 

  75. 75

    Hur, E. et al. Osteopontin induced relapse and progression of autoimmune brain disease via enhanced survival of activated T cells. Nat. Immunol. 8, 74–83 (2006).

    Article  Google Scholar 

  76. 76

    Kennedy, J. et al. Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4–CD8-T cells. J. Interferon Cytokine Res. 16, 611–617 (1996).

    CAS  Article  Google Scholar 

  77. 77

    Tartour, E. et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 59, 3698–3704 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

I thank R. Coffman and T. Mosmann, whose work inspired this review, for their constructive comments. I appreciate the input from H. Cantor, A. Zlotnik and Lee and Len Herzenberg.

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Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nat Med 13, 139–145 (2007). https://doi.org/10.1038/nm1551

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