Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

被引：119

作者：

Ichiyama, Kenji ^{[1
,2
]}

Sekiya, Takashi ^{[1
,2
]}

Inoue, Naoko ^{[1
,2
]}

Tamiya, Taiga ^{[1
,2
]}

Kashiwagi, Ikko ^{[1
,2
]}

Kimura, Akihiro ^{[1
,2
]}

Morita, Rimpei ^{[1
,2
]}

Muto, Go ^{[1
,2
]}

Shichita, Takashi ^{[1
,2
]}

Takahashi, Reiko ^{[1
,2
]}

Yoshimura, Akihiko ^{[1
,2
]}

机构：

[1] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan

[2] Japan Sci & Technol Agcy, CREST, Chiyoda Ku, Tokyo 1020075, Japan

来源：

IMMUNITY | 2011年 / 34卷 / 05期

关键词：

ROR-GAMMA-T; TGF-BETA; T(H)17 DIFFERENTIATION; AUTOIMMUNE INFLAMMATION; TH17; DIFFERENTIATION; NUCLEAR RECEPTORS; MOLECULAR-BASIS; GENE; ACTIVATION; LINEAGE;

D O I：

10.1016/j.immuni.2011.02.021

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Transforming growth factor-beta (TGF-beta) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-beta through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-beta via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-beta in Th17 cell induction in primary T cells. Eomes suppressed Rorc and II17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-beta via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation.

引用

页码：741 / 754

页数：14

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