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J Exp Med. 2009 Oct 26;206(11):2407-16. doi: 10.1084/jem.20082286. Epub 2009 Sep 28.

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

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  • 1Department of Molecular Genetics, Microbiology, and Immunology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.

Erratum in

  • J Exp Med. 2009 Dec 21;206(13):3157.

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) beta, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-beta exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-beta 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-beta had no effect on the expression of retinoic acid receptor-related orphan nuclear receptor gammat, 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-beta had no effect, suggesting that TGF-beta 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-beta antibodies. Collectively, these data provide evidence that TGF-beta is not directly required for the molecular orchestration of Th17 cell differentiation.

PMID:
19808254
PMCID:
PMC2768861
DOI:
10.1084/jem.20082286
[PubMed - indexed for MEDLINE]
Free PMC Article
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