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

被引：177

作者：

Das, Jyoti ^{[1
,4
]}

Ren, Guangwen ^{[1
]}

Zhang, Liying ^{[1
]}

Roberts, Arthur I. ^{[1
]}

Zhao, Xin ^{[1
]}

Bothwell, Alfred L. M. ^{[2
]}

Van Kaer, Luc ^{[3
]}

Shi, Yufang ^{[1
,5
]}

Das, Gobardhan ^{[6
]}

机构：

[1] Univ Med & Dent New Jersey, Dept Microbiol Mol Genet & Immunol, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA

[2] Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA

[3] Vanderbilt Univ, Dept Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA

[4] Inst Mol Med, New Delhi 110020, India

[5] Chinese Acad Sci, Shanghai Jiao Tong Univ, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol,Inst Hlth Sci,Sch Med, Shanghai 200025, Peoples R China

[6] Int Ctr Genet Engn & Biotechnol, Immunol Grp, New Delhi 110067, India

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2009年 / 206卷 / 11期

基金：

美国国家卫生研究院; 美国国家航空航天局;

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; IL-17-PRODUCING T-CELLS; CENTRAL-NERVOUS-SYSTEM; TGF-BETA; T(H)17 CELLS; TH2; CELLS; INFLAMMATION; PATHWAY; INTERLEUKIN-6; LINEAGE;

D O I：

10.1084/jem.20082286

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 gamma 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-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.

引用

页码：2407 / 2416

页数：10

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