Article | Published:

Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Nature Immunology volume 12, pages 247254 (2011) | Download Citation

Abstract

Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (TH17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

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Acknowledgements

We thank J. Simone, J. Lay and the National Institute of Arthritis, Musculoskeletal and Skin Diseases Laboratory Animal Care and Use Section staff for technical support; D. Levy (New York University) for mice with loxP-flanked Stat3 alleles; C. Dong (MD Anderson) for IL-17F–RFP reporter mice; W. Ouyang (Genentech) for monoclonal anti-IL-22; and S. Kuchen, F.C. Eberle and K. Tarbell for comments on the manuscript. Supported by the Intramural Research programs of National Institute of Arthritis, Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases.

Author information

Affiliations

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

    • Xiang-Ping Yang
    • , Kamran Ghoreschi
    • , Scott M Steward-Tharp
    • , Kiyoshi Hirahara
    • , Hong-Wei Sun
    • , Golnaz Vahedi
    • , Yuka Kanno
    • , John J O'Shea
    •  & Arian Laurence
  2. Laser Capture Microdissection Core Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Jaime Rodriguez-Canales
  3. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Jinfang Zhu
  4. Mucosal Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • John R Grainger
  5. Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Lai Wei

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Contributions

X.-P.Y. designed and did experiments, analyzed and wrote the manuscript; K.G. designed and did experiments and helped write the manuscript; S.M.S.-T. helped analyze gut lymphocytes; J.R.-C. examined the histopathology; J.Z., K.H. and J.R.G. provided mice and helped with experiments; Y.K. did ChIP-seq experiments; L.W., H.-W.S., Y.K. and G.V. analyzed data from the ChIP-seq and microarray experiments; J.J.O.'S. designed experiments, analyzed all acquired data and helped write the manuscript; and A.L. designed, did or interpreted all experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arian Laurence.

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DOI

https://doi.org/10.1038/ni.1995

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