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

Nature Immunology volume 8, pages 967974 (2007) | Download Citation

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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.

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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.

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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

Affiliations

  1. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, 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, Maryland 20892, USA.

    • Rosanne Spolski
    •  & Warren J Leonard
  3. Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.

    • Roy Min
    •  & Dan R Littman
  4. Departments of Pathology and Microbiology, New York University School of Medicine, New York, New York 10016, USA.

    • David E Levy
    •  & Dan R Littman

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan R Littman.

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DOI

https://doi.org/10.1038/ni1488

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