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:

IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways

Nature Immunology volume 8, pages 967–974 (2007)Cite this article

This article has been updated

Abstract

T helper cells that produce interleukin 17 (IL-17; 'TH-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-β (TGF-β). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4+ T cells. Both IL-21 and IL-23, along with TGF-β, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of TH-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORγt, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-β, amplify RORγt-dependent differentiation of TH-17 cells.

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: Differential requirement for RORγt in the induction of IL-21 and IL-23R by IL-6.
Figure 2: IL-23–IL-23R signaling induces RORγt and IL-17.
Figure 3: IL-21 signaling induces RORγt, IL-17 and IL-17F.
Figure 4: IL-21 contributes to TH-17 cell differentiation and functions in a self-amplifying loop.
Figure 5: STAT3 is required for IL-21-induced IL-17 expression.
Figure 6: STAT3 and RORγt act together to induce maximum IL-17 expression.

Similar content being viewed by others

Change history

  • 05 July 2007

    In the version of this article initially published online, the affiliation for the eighth author, Warren J. Leonard, is incorrect. The correct affiliation should be ‘2’ (Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, USA). The error has been corrected for all versions of the article.

References

  1. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  Google Scholar 

  2. Harrington, L.E., Mangan, P.R. & Weaver, C.T. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr. Opin. Immunol. 18, 349–356 (2006).

    Article  CAS  Google Scholar 

  3. 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 

  4. Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  5. Kaplan, M.H., Sun, Y.L., Hoey, T. & Grusby, M.J. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382, 174–177 (1996).

    Article  CAS  Google Scholar 

  6. Thierfelder, W.E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).

    Article  CAS  Google Scholar 

  7. Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat. Immunol. 3, 549–557 (2002).

    Article  CAS  Google Scholar 

  8. Kaplan, M.H., Schindler, U., Smiley, S.T. & Grusby, M.J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313–319 (1996).

    Article  CAS  Google Scholar 

  9. Takeda, K. et al. Essential role of Stat6 in IL-4 signalling. Nature 380, 627–630 (1996).

    Article  CAS  Google Scholar 

  10. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  Google Scholar 

  11. 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 

  12. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

    Article  CAS  Google Scholar 

  13. 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 

  14. Witowski, J., Ksiazek, K. & Jorres, A. Interleukin-17: a mediator of inflammatory responses. Cell. Mol. Life Sci. 61, 567–579 (2004).

    Article  CAS  Google Scholar 

  15. 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 

  16. Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  Google Scholar 

  17. 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 

  18. Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827–2833 (2004).

    Article  CAS  Google Scholar 

  19. 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. Trinchieri, G., Pflanz, S. & Kastelein, R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19, 641–644 (2003).

    Article  CAS  Google Scholar 

  25. 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 

  26. Bettelli, E., Oukka, M. & Kuchroo, V.K. TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

    Article  CAS  Google Scholar 

  27. Kikly, K., Liu, L., Na, S. & Sedgwick, J.D. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr. Opin. Immunol. 18, 670–675 (2006).

    Article  CAS  Google Scholar 

  28. 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 

  29. Kullberg, M.C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).

    Article  CAS  Google Scholar 

  30. 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 

  31. 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).

    Article  CAS  Google Scholar 

  32. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Colgan, J. & Rothman, P. All in the family: IL-27 suppression of TH-17 cells. Nat. Immunol. 7, 899–901 (2006).

    Article  CAS  Google Scholar 

  35. Leonard, W.J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5, 688–698 (2005).

    Article  CAS  Google Scholar 

  36. Mehta, D.S., Wurster, A.L. & Grusby, M.J. Biology of IL-21 and the IL-21 receptor. Immunol. Rev. 202, 84–95 (2004).

    Article  CAS  Google Scholar 

  37. Zeng, R. et al. The molecular basis of IL-21-mediated proliferation. Blood 109, 4135–4142 (2007).

    Article  CAS  Google Scholar 

  38. Pesce, J. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116, 2044–2055 (2006).

    Article  CAS  Google Scholar 

  39. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Wu, Z. et al. Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity. Mol. Cell. Biol. 25, 9741–9752 (2005).

    Article  CAS  Google Scholar 

  42. Lee, C.K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17, 63–72 (2002).

    Article  CAS  Google Scholar 

  43. Yasukawa, H., Sasaki, A. & Yoshimura, A. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18, 143–164 (2000).

    Article  CAS  Google Scholar 

  44. Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Peluso, I. et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J. Immunol. 178, 732–739 (2007).

    Article  CAS  Google Scholar 

  47. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).

    Article  CAS  Google Scholar 

  48. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    Article  CAS  Google Scholar 

  49. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  50. Zhou, L., Nazarian, A.A. & Smale, S.T. Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway. Mol. Cell. Biol. 24, 2385–2396 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Lopez for assistance with cell sorting, and Y. Kluger and J. Wang for assistance in microarray analysis. T-bet–IRES–GFP was from S. Reiner (University of Pennsylvania), STAT3C and STAT3F cDNA were from D.A. Frank (Harvard University), and anti-IL-17F was from C. Dong (MD Anderson Cancer Center). Supported by the Irvington Institute for Immunological Research (L.Z.), the Crohn's and Colitis Foundation of America (I.I.I.), the Leukemia and Lymphoma Society (T.E.), the Howard Hughes Medical Institute (D.R.L.), the Sandler Program for Asthma Research (D.R.L.), the Helen and Martin Kimmel Center for Biology and Medicine (D.R.L.) and the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health (R.S. and W.J.L.).

Author information

Authors and Affiliations

  1. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, 10016, New York, USA

    Liang Zhou, Ivaylo I Ivanov, Roy Min, Kevin Shenderov, Takeshi Egawa & Dan R Littman

  2. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, 20892, Maryland, USA

    Rosanne Spolski & Warren J Leonard

  3. Howard Hughes Medical Institute, New York University School of Medicine, New York, 10016, New York, USA

    Roy Min & Dan R Littman

  4. Departments of Pathology and Microbiology, New York University School of Medicine, New York, 10016, New York, USA

    David E Levy & Dan R Littman

Authors
  1. Liang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivaylo I Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosanne Spolski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roy Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin Shenderov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Egawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David E Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Warren J Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dan R Littman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.Z. did all the in vitro experiments, with assistance from R.M. and K.S., and contributed to the writing of the manuscript; I.I.I. and R.S. did the in vivo studies; T.E. contributed to microarray analysis; D.E.L. contributed mice and advice on STAT3 experiments; W.J.L. provided the IL-21R mutant mice and participated in experimental design; and D.R.L. directed the study and wrote the manuscript.

Corresponding author

Correspondence to Dan R Littman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1-4 (PDF 118 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, L., Ivanov, I., Spolski, R. 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). https://doi.org/10.1038/ni1488

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1488

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