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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
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
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).
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).
Coffman, R.L. Origins of the TH1-TH2 model: a personal perspective. Nat. Immunol. 7, 539–541 (2006).
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).
Klein, J. & Nagy, Z. Trouble in the J-land. Nature 300, 12–13 (1982).
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).
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).
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).
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).
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).
Benacerraf, B. & McCluskey, R. Methods of immunologic injury to tissues. Annu. Rev. Microbiol. 17, 263–284 (1963).
Waksman, B.H. Auto-immunization and the lesions of autoimmunity. Medicine (Baltimore) 41, 93–141 (1962).
Paterson, P.Y. Transfer of allergic encephalomyelitis by means of lymph node cells. J. Exp. Med. 111, 119–136 (1960).
Billiau, A. et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J. Immunol. 140, 1506–1510 (1988).
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).
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).
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).
Krakowski, M. & Owens, T. Interferon-γ confers resistance to EAE. Eur. J. Immunol. 26, 1641–1646 (1996).
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).
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).
Zamvil, S. et al. T cell clones specific for myelin basic protein induce chronic relapsing EAE and demyelination. Nature 317, 355–358 (1985).
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).
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).
Liu, J. et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat. Med. 4, 78–83 (1998).
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).
Feldmann, M. & Steinman, L. Design of effective immunotherapy for human autoimmunity. Nature 435, 612–619 (2005).
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).
Kuhn, T.S. The Structure of Scientific Revolutions. (Univ. Chicago Press, Chicago, 1962).
Williams, R. Bone destruction by TH17. J. Exp. Med. 203, 2567 (2006).
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).
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).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
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).
Tato, C.M. & O'Shea, J. What does it mean to be just 17? Nature 441, 166–168 (2006).
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).
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).
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).
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).
Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).
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).
Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).
Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).
Steinman, L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat. Rev. Drug Discov. 4, 510–519 (2005).
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).
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).
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).
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).
Rangachari, M. et al. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J. Exp. Med. 203, 2009–2019 (2006).
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).
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).
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).
Mangan, P.R. et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–234 (2006).
Ye, P. et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am. J. Respir. Cell Mol. Biol. 25, 335–340 (2001).
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).
Schnyder-Candrian, S., et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).
Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).
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).
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).
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).
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).
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).
Duerr, R., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
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).
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).
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).
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).
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).
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).
Fong, A. & Mosmann, T. The role of interferon-γ in delayed-type hypersensitivity mediated by TH1 clones. J. Immunol. 147, 2887–2893 (1989).
Lotze, M.T. & Tracey, K. High-mobility group box protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331–342 (2005).
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).
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).
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).
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).
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.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1551
This article is cited by
-
Activation of the IL-17/TRAF6/NF-κB pathway is implicated in Aβ-induced neurotoxicity
BMC Neuroscience (2023)
-
ITK independent development of Th17 responses during hypersensitivity pneumonitis driven lung inflammation
Communications Biology (2022)
-
Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases
Cell Death & Disease (2022)
-
IL-23R gene polymorphisms in rheumatoid arthritis
Rheumatology International (2022)
-
“Environmental risk factors associated with juvenile idiopathic arthritis associated uveitis: a systematic review of the literature”
Journal of Ophthalmic Inflammation and Infection (2021)