The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns

被引:123
作者
Oestreich, Kenneth J. [1 ]
Huang, Albert C. [1 ,2 ]
Weinmann, Amy S. [1 ,2 ]
机构
[1] Univ Washington, Dept Immunol, Seattle, WA 98195 USA
[2] Univ Washington, Mol & Cellular Biol Program, Seattle, WA 98195 USA
关键词
TRANSCRIPTION FACTOR GATA-3; INTERFERON-GAMMA; CELL-DIFFERENTIATION; CYTOKINE SIGNALING-1; TARGET GENES; SUPPRESSOR; COMMITMENT; SOCS-3; FATE; PLASTICITY;
D O I
10.1084/jem.20102144
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The T-box transcription factor T-bet is important for the differentiation of naive CD4(+) T helper cells (Th cells) into the Th1 phenotype. Much is known about T-bet's role as a transcriptional activator, but less is known about the mechanisms by which T-bet functionally represses alternative Th cell genetic programs. In this study, we first identify Socs1, Socs3, and Tcf7 (TCF-1) as gene targets that are negatively regulated by T-bet. Significantly, T-bet's role in the repression of these genes is through a direct interaction with their promoters. Consistent with this, we identified two T-bet DNA-binding elements in the Socs1 promoter that are functionally used to down-regulate transcription in primary Th1 cells. Importantly, T-bet's novel role in transcriptional repression is because of its ability to physically associate with, and functionally recruit, the transcriptional repressor Bcl-6 to a subset of promoters. Furthermore, T-bet functionally recruits Bcl-6 to the Ifng locus in late stages of Th1 differentiation to repress its activity, possibly to prevent the overproduction of IFN-gamma, which could result in autoimmunity. Collectively, these data establish a novel mechanism for T-bet-mediated gene repression in which two lineage-defining transcription factors, one a classical activator and one a repressor, collaborate to promote and properly regulate Th1 development.
引用
收藏
页码:1001 / 1013
页数:13
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