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* Department of Gene and Cell Medicine,
Department of Surgery,
Immunology Institute, and
The Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029
Th1 and Th17 cells are crucial in immune regulation and autoimmune disease development. By adding Stat6 deficiency to T-bet deficiency, and thus negating effects from elevated levels of IL-4/Stat6/GATA3 Th2 signals in T-bet-deficient cells, we investigated the signals important for Th1 and Th17 cell differentiation and their role in colitis development. The data reveal that Eomesodermin compensates T-bet deficiency for IFN-
and Th1 development. However, without T-bet, IFN- production and Th1 differentiation are susceptible to inhibition by IL-6 and TGFβ. As a result, Th17 development is strongly favored, the threshold for TGFβ requirement is lowered, and IL-6 drives Th17 differentiation, elucidating a critical role for T-bet in directing T cell differentiation to Th1 vs Th17. In contrast to IL-6 plus TGFβ-driven Th17, IL-6-driven Th17 cells do not express IL-10 and they induce a more intense colitis. Naive CD4 T cells deficient in Stat6 and T-bet also induce a Th17-dominant colitis development in vivo. Our data provide new insights into the choice between Th1 and Th17 development and their roles in autoimmunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 AI 62855 (to Y.D.), AI 41428 (to J.S.B.), and AI 62765 (to J.S.B.).
2 Address correspondence and reprint requests to Dr. Yaozhong Ding, Department of Gene and Cell Medicine, Box 1496, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. E-mail address: yaozhong.ding{at}mssm.edu
3 Abbreviations used in this paper: Eomes, Eomesodermin; DKO, double knockout.
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