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.

  • Article
  • Published:

The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo

Nature Immunology volume 10, pages 314–324 (2009)Cite this article

Abstract

Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (TH-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of TH-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, TH-17 development was stalled at the early activation stage. TH-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor α-chain. These defects were associated with less proliferation; consequently, fewer effector TH-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.

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: Il23ra−/− CD4+ T cells do not accumulate in the inflamed CNS.
Figure 2: Il23ra−/− T cells have lower IL-17 production after T cell priming.
Figure 3: Early activation of TH-17 cells is normal but effector responses are impaired for Il23ra−/− T cells.
Figure 4: Full differentiation of effector TH-17 cells requires IL-23R in vivo.
Figure 5: IL-23 promotes the effector cytokine profile of TH-17.
Figure 6: IL-23R is not required for the development of effector TH1 cells.
Figure 7: Timing of the requirement for IL-23R during TH-17 differentiation.
Figure 8: The proliferation of IL-17+ cells is lower in the absence of IL-23R.

Similar content being viewed by others

References

  1. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    Article  CAS  Google Scholar 

  2. 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 

  3. McKenzie, B.S., Kastelein, R.A. & Cua, D.J. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 27, 17–23 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Smith, R.L. et al. Polymorphisms in the IL-12β and IL-23R genes are associated with psoriasis of early onset in a UK cohort. J. Invest. Dermatol. 128, 1325–1327 (2007).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    Article  CAS  Google Scholar 

  15. Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  Google Scholar 

  16. 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 

  17. Yang, X.O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007).

    Article  CAS  Google Scholar 

  18. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

    Article  CAS  Google Scholar 

  19. Elson, C.O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

    Article  CAS  Google Scholar 

  20. Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).

    Article  CAS  Google Scholar 

  21. Chan, J.R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).

    Article  CAS  Google Scholar 

  22. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    Article  CAS  Google Scholar 

  23. Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).

    Article  CAS  Google Scholar 

  24. Harris, T.J. et al. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313–4317 (2007).

    Article  CAS  Google Scholar 

  25. 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 

  26. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  Google Scholar 

  27. Veldhoen, M., Hocking, R.J., Flavell, R.A. & Stockinger, B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7, 1151–1156 (2006).

    Article  CAS  Google Scholar 

  28. Boyman, O., Purton, J.F., Surh, C.D. & Sprent, J. Cytokines and T-cell homeostasis. Curr. Opin. Immunol. 19, 320–326 (2007).

    Article  CAS  Google Scholar 

  29. Kondrack, R.M. et al. Interleukin 7 regulates the survival and generation of memory CD4 cells. J. Exp. Med. 198, 1797–1806 (2003).

    Article  CAS  Google Scholar 

  30. Li, J., Huston, G. & Swain, S.L. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J. Exp. Med. 198, 1807–1815 (2003).

    Article  CAS  Google Scholar 

  31. Fritsch, R.D. et al. Stepwise differentiation of CD4 memory T cells defined by expression of CCR7 and CD27. J. Immunol. 175, 6489–6497 (2005).

    Article  CAS  Google Scholar 

  32. Bird, J.J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).

    Article  CAS  Google Scholar 

  33. Villarino, A.V. et al. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp. Med. 204, 65–71 (2007).

    Article  CAS  Google Scholar 

  34. Dooms, H., Wolslegel, K., Lin, P. & Abbas, A.K. Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7Rα-expressing cells. J. Exp. Med. 204, 547–557 (2007).

    Article  CAS  Google Scholar 

  35. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  Google Scholar 

  36. Lieberman, L.A. et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J. Immunol. 173, 1887–1893 (2004).

    Article  CAS  Google Scholar 

  37. Miller, S.D. et al. Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol. Rev. 144, 225–244 (1995).

    Article  CAS  Google Scholar 

  38. Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).

    Article  CAS  Google Scholar 

  39. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    Article  CAS  Google Scholar 

  40. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    Article  CAS  Google Scholar 

  41. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    Article  CAS  Google Scholar 

  42. Chackerian, A.A. et al. Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect. Immun. 74, 6092–6099 (2006).

    Article  CAS  Google Scholar 

  43. Higgins, S.C., Jarnicki, A.G., Lavelle, E.C. & Mills, K.H. TLR4 mediates vaccine-induced protective cellular immunity to Bordetella pertussis: role of IL-17-producing T cells. J. Immunol. 177, 7980–7989 (2006).

    Article  CAS  Google Scholar 

  44. Khader, S.A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).

    Article  CAS  Google Scholar 

  45. 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 

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

    Article  CAS  Google Scholar 

  47. Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  48. Krueger, G.G. et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the assistance of B. Desai and S. Jungers with flow cytometry sorting, and C. Diveu and R. Kastelein for discussions.

Author information

Authors and Affiliations

  1. Schering-Plough Biopharma, Palo Alto, 94304, California, USA

    Mandy J McGeachy, Yi Chen, Cristina M Tato, Barbara Joyce-Shaikh, Wendy M Blumenschein, Terrill K McClanahan & Daniel J Cua

  2. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Arian Laurence & John J O'Shea

Authors
  1. Mandy J McGeachy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina M Tato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arian Laurence
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara Joyce-Shaikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wendy M Blumenschein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Terrill K McClanahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John J O'Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel J Cua
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.J.M. and D.J.C. designed the experiments and wrote the manuscript; M.J.M. did most of the experiments with assistance from B.J.-S. and Y.C.; C.M.T. did toxoplasma experiments; A.L. and J.J.O. provided Cre-STAT3–knockdown data; and W.M.B. and T.K.M. analyzed gene expression.

Corresponding author

Correspondence to Daniel J Cua.

Ethics declarations

Competing interests

M.J.M., Y.C., C.M.T., B.J-S., W.B. T.M. and D.J.C. are employed by Schering-Plough Biopharma.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 352 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

McGeachy, M., Chen, Y., Tato, C. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat Immunol 10, 314–324 (2009). https://doi.org/10.1038/ni.1698

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1698

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