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¹ Department of Molecular Genetics, Microbiology, and Immunology, Robert Wood Johnson Medical School–University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854
² Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
³ Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
⁴ Institute of Molecular Medicine, New Delhi 110020, India
⁵ Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
⁶ Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India

CORRESPONDENCE Yufang Shi: shiyufang2{at}gmail.com OR Gobardhan Das: dasgo{at}icgeb.res.in

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor t, a Th17-specific transcription factor. Interestingly, in Stat-6^–/–T-bet^–/– mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6^–/–T-bet^–/– mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

Y. Shi and G. Das contributed equally to this paper.

Abbreviations used: EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; ROR, retinoic acid receptor–related orphan nuclear receptor; TGF-βRIIDN, dominant-negative TGF-βRII.

© 2009 Das et al.
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