Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

Jyoti Das, Guangwen Ren, Liying Zhang, Arthur I. Roberts, Xin Zhao, Alfred L.M. Bothwell, Luc Van Kaer, Yufang Shi, Gobardhan Das

Research output: Contribution to journalArticle

163 Scopus citations

Abstract

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 γt, 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.

Original languageEnglish (US)
Pages (from-to)2407-2416
Number of pages10
JournalJournal of Experimental Medicine
Volume206
Issue number11
DOIs
StatePublished - Oct 26 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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