Abstract
Transcription factors of the STAT family are critical in the cytokine-mediated functional differentiation of CD4+ helper T cells. Signaling inhibitors of the SOCS family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by directly binding to the Il9 promoter. Our data thus demonstrate a critical role for CIS in controlling the proallergic generation of helper T cells.
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Acknowledgements
We thank S. Rivera and J. Parker-Thornburg of the MD Anderson Genetic Engineered Mouse Facility for help in generating gene-targeted mice; A.Y. Rudensky (Memorial Sloan-Kettering Cancer Center) for Foxp3-GFP and Foxp3-Cre mice; C.B. Wilson (University of Washington) for CD4-Cre mice; M. Kaplan (Indiana University School of Medicine) for the STAT6VT-expressing construct; and members of the Dong laboratory for help and discussion. Supported by the US National Institutes of Health (C.D., S.S.W., D.W. and D.B.C.), the Leukemia and Lymphoma Society (C.D. and D.W.), MD Anderson Cancer Center (C.D.), the Biology of Inflammation Center at Baylor College of Medicine (D.B.C.), the American Heart Association, the American Cancer Society (X.O.Y.), the Shanghai Board of Health Foundation, Shanghai Jiao Tong University (X.N.) and the Ministry of Education of China (J.P.).
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C.D. and X.O.Y. conceived of the project, designed the experiments and wrote the manuscript; X.O.Y., H.Z. and B.-S.K. did most of the experiments; and X.N., J.P., Y.C., R.K., Y.-H.L., S.H.C., D.B.C., D.W. and S.S.W. participated in specific experiments.
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Yang, X., Zhang, H., Kim, BS. et al. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat Immunol 14, 732–740 (2013). https://doi.org/10.1038/ni.2633
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DOI: https://doi.org/10.1038/ni.2633
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