Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Type 17 T helper cells—origins, features and possible roles in rheumatic disease

Nature Reviews Rheumatology volume 5, pages 325–331 (2009)Cite this article

Abstract

Type 17 T helper (TH17) cells are a population of CD4+ effector T cells that are distinct from TH1 and TH2 cells owing to their ability to produce interleukin (IL)-17. Although TH1 and TH2 cells are similar in mice and humans, TH17 cells differ in several ways. The differentiation of mouse TH17 cells requires transforming growth factor β and IL-6, whereas human naive T cells can develop into TH17 cells in the presence of IL-1β and IL-23 alone, transforming growth factor β having an indirect role in their development via the selective inhibition of TH1 cell expansion. In both mice and humans, a late developmental plasticity of TH17 cells towards the TH1 lineage has been shown. Mainly based on mouse gene knockout studies, TH17 lymphocytes have been found to have a pathogenic role in several autoimmune disorders; however, whether human autoimmune disorders, including rheumatoid arthritis (RA) and psoriasis, are prevalently TH1-mediated or TH17-mediated, is still unclear. Research suggests that both TH1 and TH17 cells are involved in RA pathogenesis, raising the possibility that interventions that target both the IL-23–IL-17 (TH17) and the IL-12–interferon γ (TH1) axes might be successful future therapeutic approaches for RA.

Key Points

  • It is our opinion that the origin and development of type 17 T helper (TH17) cells in humans is different than in mice

  • Human TH17 cells can be induced to produce interferon-γ in the presence of interleukin (IL)-12, thus becoming TH17/TH1 cells

  • TH17 cells are associated with several immune-mediated diseases, particularly psoriasis and rheumatoid arthritis, owing to the pleiotropic effects exerted by IL-17 and related-cytokines on osteoblasts, B cells and monocytes

  • The pathogenesis of rheumatoid arthritis is more complex than previously thought; both TH17 and TH1 cells are probably involved in the maintenance of inflammation that leads to joint destruction

  • Immune-mediated diseases could perhaps be treated more effectively by therapeutic interventions that target both the IL-23–IL-17 (TH17) and IL12–interferon-γ (TH1) axes, rather than just a single pathway

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distinct origin of mouse and human TH17 cells.
Figure 2: Schematic of the possible pathogenic role of TH17 cells and TH1 cells in rheumatoid arthritis.
Figure 3: Schematic of the cytokines that are targeted by currently available biologic drugs.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Romagnani, S. Human TH1 and TH2 subsets: doubt no more. Immunol. Today 12, 256–257 (1991).

    Article  CAS  Google Scholar 

  3. Romagnani, S. The TH1/TH2 paradigm. Immunol. Today 18, 263–266 (1997).

    Article  CAS  Google Scholar 

  4. Gately, M. K. et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu. Rev. Immunol. 16, 495–521 (1998).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Murphy, C. A. et al. Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1958 (2003).

    Article  CAS  Google Scholar 

  7. Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995).

    Article  CAS  Google Scholar 

  8. Dong, C. Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol. Rev. 226, 80–86 (2008).

    Article  CAS  Google Scholar 

  9. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 44, 235–238 (2006).

    Article  Google Scholar 

  10. Mangan, P. R. et al. Transforming growth factor-beta induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  11. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGF-beta in the context of an inflammatory cytokine milieu supports differentiation of IL-17-producing T cells. Immunity 25, 179–189 (2006).

    Article  Google Scholar 

  12. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 44, 235–238 (2006).

    Article  Google Scholar 

  13. Huber, M. et al. IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc. Natl Acad. Sci. USA 105, 20846–20851 (2008).

    Article  CAS  Google Scholar 

  14. Veldhoen, M., Hirota, K., Christensen, J., O'Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).

    Article  CAS  Google Scholar 

  15. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatopry IL-17+ T helper cells. Cell 126, 1121–1131 (2006).

    Article  CAS  Google Scholar 

  16. Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  Google Scholar 

  17. Chen, Z., Laurence, A. & O'Shea, J. J. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin. Immunol. 19, 400–408 (2007).

    Article  CAS  Google Scholar 

  18. Ouyang, W., Koli, J. K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  Google Scholar 

  19. Dubin, P. J. & Kolls, J. K. Th17 cytokines and mucosal immunity. Immunol. Rev. 226, 160–171 (2008).

    Article  CAS  Google Scholar 

  20. Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).

    Article  CAS  Google Scholar 

  21. Oukka, M. Th17 cells in immunity and autoimmunity. Ann. Rheum. Dis. 67 (Suppl. 3), 26–29 (2008).

    Google Scholar 

  22. Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).

    Article  CAS  Google Scholar 

  23. Wilson, N. J. et al. Development, cytokine profile and function of human interleukin-17-producing helper T cells. Nat. Immunol. 8, 950–957 (2007).

    Article  CAS  Google Scholar 

  24. Evans, H. G., Suddason, T., Jackson, I., Taams, L. S. & Lord, G. M. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc. Natl Acad. Sci. USA 104, 17034–17039 (2007).

    Article  CAS  Google Scholar 

  25. van Beelen, A. J. et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660–669 (2007).

    Article  CAS  Google Scholar 

  26. Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human Th17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat. Immunol. 9, 641–649 (2008).

    Article  CAS  Google Scholar 

  27. Volpe, E. et al. A critical function for transforming growth factor-β, interleukin-23 and proinflammatory cytokines in driving and modulating human Th17 responses. Nat. Immunol. 9, 650–957 (2008).

    Article  CAS  Google Scholar 

  28. Yang, L. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008).

    Article  CAS  Google Scholar 

  29. Cosmi, L. et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 205, 1903–1916 (2008).

    Article  CAS  Google Scholar 

  30. de Beaucoudrey, L. et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J. Exp. Med. 205, 1543–1550 (2008).

    Article  CAS  Google Scholar 

  31. Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008).

    Article  CAS  Google Scholar 

  32. Milner, J. D. et al. Impaired Th17 differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

    Article  CAS  Google Scholar 

  33. Santarlasci, V. et al. TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur. J. Immunol. 39, 207–215 (2009).

    Article  CAS  Google Scholar 

  34. Kroenke, M. A., Carlson, T. J., Andjelkovic, A. V. & Segal, B. M. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J. Exp. Med. 205, 1535–1541 (2009).

    Article  Google Scholar 

  35. Doodes, P. D. et al. Development of proteoglycan-induced arthritis is independent of IL-17. J. Immunol. 181, 329–337 (2008).

    Article  CAS  Google Scholar 

  36. Luger, D. et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799–810 (2008).

    Article  CAS  Google Scholar 

  37. Collison, L. W. & Vignali, D. A. Interleukin-35: odd one out or part of the family? Immunol. Rev. 226, 248–262 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. 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).

    Article  CAS  Google Scholar 

  40. Hofstetter, H. H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell. Immunol. 237, 123–130 (2005).

    Article  CAS  Google Scholar 

  41. Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

    Article  CAS  Google Scholar 

  42. Zhang, Z. et al. After interleukin-12p40, are interleukin-23 and interleukin-17 the next therapeutic targets for inflammatory bowel disease? Int. Immunopharmacol. 7, 409–416 (2007).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Fuss, I. J. et al. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm. Bowel Dis. 12, 9–15 (2006).

    Article  Google Scholar 

  45. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    Article  CAS  Google Scholar 

  46. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    Article  CAS  Google Scholar 

  47. Shi, G. et al. Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J. Immunol. 181, 7205–7213 (2008).

    Article  CAS  Google Scholar 

  48. Bending, D. et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J. Clin. Invest. [doi:10.1172/JCI37865] (2009).

  49. Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25−Foxp3− T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J. Immunol. 178, 6725–6729 (2007).

    Article  CAS  Google Scholar 

  50. Koenen, H. J. et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112, 2340–2352 (2008).

    Article  CAS  Google Scholar 

  51. Beriou, G. et al. IL-17 producing human peripheral regulatory T cells retain suppressive function. Blood [doi:10.1182/blood-2008-10-183251] (2009).

  52. Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl Acad. Sci. USA 100, 5986–5990 (2003).

    Article  CAS  Google Scholar 

  53. Hirota, K. et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J. Exp. Med. 204, 41–47 (2007).

    Article  CAS  Google Scholar 

  54. Fujimoto, M. et al. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 58, 3710–3719 (2008).

    Article  CAS  Google Scholar 

  55. Young, D. A. et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 56, 1152–1163 (2007).

    Article  CAS  Google Scholar 

  56. Mathur, A. N. et al. STAT3 and STAT4 direct development of IL-17-secreting Th cells. J. Immunol. 178, 4901–4907 (2007).

    Article  CAS  Google Scholar 

  57. Hildner, K. M. et al. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J. Immunol. 178, 3427–3436 (2007).

    Article  CAS  Google Scholar 

  58. Geboes, L. et al. Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum. 60, 390–395 (2009).

    Article  CAS  Google Scholar 

  59. Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    Article  CAS  Google Scholar 

  60. Piskin, G., Sylva-Steenland, R. M., Bos, J. D. & Teunissen, M. B. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J. Immunol. 176, 1908–1915 (2006).

    Article  CAS  Google Scholar 

  61. Capon, F. et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum. Genet. 122, 201–206 (2007).

    Article  CAS  Google Scholar 

  62. Nair, R. P. et al. Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J. Invest. Dermatol. 128, 1653–1661 (2008).

    Article  CAS  Google Scholar 

  63. Zaba, L. C. et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 204, 3183–3194 (2007).

    Article  CAS  Google Scholar 

  64. Arican, O., Sasmaz, S. & Ciragil, P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 5, 273–279 (2005).

    Article  Google Scholar 

  65. Leonardi, C. L. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371, 1665–1674 (2008).

    Article  CAS  Google Scholar 

  66. Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675–1684 (2008).

    Article  CAS  Google Scholar 

  67. Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).

    Article  CAS  Google Scholar 

  68. Sato, K. et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat. Med. 12, 1410–1416 (2006).

    Article  CAS  Google Scholar 

  69. Kirkham, B. W. et al. Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum. 54, 1122–1131 (2006).

    Article  CAS  Google Scholar 

  70. Bush, K. A., Farmer, K. M., Walker, J. S. & Kirkham, B. W. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum. 46, 802–805 (2002).

    Article  CAS  Google Scholar 

  71. Lubberts, E. IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41, 84–91 (2008).

    Article  CAS  Google Scholar 

  72. 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 

  73. Mauritz, N. et al. Treatment with γ-interferon triggers the onset of collagen arthritis in mice. Arthritis Rheum. 31, 1297–1304 (1988).

    Article  CAS  Google Scholar 

  74. Cooper, S. M., Sriram, S. & Ranges, G. E. Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma. J. Immunol. 141, 1958–1962 (1988).

    CAS  PubMed  Google Scholar 

  75. Singh, R., Aggarwal, A. & Misra, R. Th1/Th17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J. Rheumatol. 34, 2285–2290 (2007).

    CAS  Google Scholar 

  76. Notley, C. A. et al. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J. Exp. Med. 205, 2491–2497 (2008).

    Article  CAS  Google Scholar 

  77. Martin-Orozco, N., Chung, Y., Chang, S. H., Wang, Y. H. & Dong, C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur. J. Immunol. 39, 216–224 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The studies by F. Annunziato, L. Cosmi, F. Liotta, E. Maggi and S. Romagnani discussed in this Review have been supported by funds from the Italian Ministry of Education (40%), the Italian Ministry of Health, the Ente Cassa di Risparmio of Florence, and EU Projects SENS-IT-IV and INNOCHEM.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Faculty of Medicine, University of Florence, Italy

    Francesco Annunziato, Lorenzo Cosmi, Francesco Liotta, Enrico Maggi & Sergio Romagnani

Authors
  1. Francesco Annunziato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lorenzo Cosmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Liotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Enrico Maggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergio Romagnani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergio Romagnani.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Annunziato, F., Cosmi, L., Liotta, F. et al. Type 17 T helper cells—origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 5, 325–331 (2009). https://doi.org/10.1038/nrrheum.2009.80

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2009.80

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing