STAT1 signaling is required for optimal Th1 cell differentiation in mice  

作　　者：MA Da HUANG Hua HUANG Zan 

机构地区：[1]The Key Laboratory of Developmental Genes and Human Disease of Education Ministry, School of Basic Medical Science, Southeast University, Nanjing 210009, China [2]Department of Cell Biology, Neurology and Anatomy, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA

出　　处：《Chinese Science Bulletin》2010年第11期1032-1040,共9页

基　　金：supported by the National Natural Science Foundation of China (Grant No. 30700412).

摘　　要：Although IFN-γ alone does not prime type I T helper cell (Th1) differentiation, the loss of IFN-γ signaling leads to impaired Th1 phenotype: IFN-γ receptor-deficient (Ifngr-/-) Th1 cells fail to permanently repress IL-4 expression. They can differentiate into IL-4-producing cells under Th2-inducing conditions. These observations suggest that IFN-γ signaling plays a critical role in si- lencing Il4 gene in Th1 cells and stabilizing Th1 phenotype. IFN-γ signaling has been further shown to inhibit IL-4 expression by inhibiting STAT6 phosphorylation. This work aims to study the mechanism by which STAT1, the downstream molecule that transduces IFN-γ signaling, may mediate suppression of IL-4 expression in Th1 cells. The results show that STAT1-deficient naive CD4+ T cells express a reduced level of IFN-γ as well as an elevated level of IL-4. These cells exhibit bias to differentiate into Th2 cells under unpolarized conditions. Under Th1-inducing conditions, STAT1-deficient naive CD4+ T cells show impaired Th1 differentiation: Stat1-/- Th1 cells express reduced levels of IFN-γ and T-bet. These cells also fail to repress the expression of IL-4 and GATA-3 and retain STAT6 signaling. More importantly, Stat1-/- Th1 cells can be effectively induced to differentiate into IL-4-producing cells under Th2-inducing conditions. Ectopic expression of T-bet in Stat1-/- Th1 cells dramatically represses their ability to do so and drastically restores IFN-γ expression, suggesting that STAT1 may inhibit IL-4 expression through T-bet. Finally, histone H3 acetylation (H3AC) and histone H3 K4 dimethylation (H3K4dim) were observed in two enhancer regions of Il4 gene locus in Stat1-/- Th1 cells, suggesting a permissive status of Il4 gene locus in these cells. Thus, this study reveals new mechanisms by which STAT1 signaling may mediate repression of Il4 gene in Th1 cells: upregulating T-bet that subsequently represses GATA3 and IL-4 expression, antagonizing STAT6 signaling, and inhibiting epigenetic modifications in Il4 gene locus.Although IFN-γ alone does not prime type I T helper cell （Th1） differentiation, the loss of IFN-T signaling leads to impaired Th1 phenotype： IFN-γ receptor-deficient （Ifngr^＋） Th1 cells fail to permanently repress IL-4 expression. They can differentiate into IL-4-producing cells under Th2-inducing conditions. These observations suggest that IFN-γ signaling plays a critical role in silencing Il4 gene in Th1 cells and stabilizing Th1 phenotype. IFN-γ signaling has been further shown to inhibit IL-4 expression by inhibiting STAT6 phosphorylation. This work aims to study the mechanism by which STAT1, the downstream molecule that transduces IFN-γ signaling, may mediate suppression of IL-4 expression in Th1 cells. The results show that STATl-deficient naive CD4^＋ T cells express a reduced level of IFN-γ as well as an elevated level of IL-4. These cells exhibit bias to differentiate into Th2 cells under unpolarized conditions. Under Th1-inducing conditions, STATl-deficient naive CD4^＋ T cells show impaired Th1 differentiation： Statl^＋ Th1 cells express reduced levels of IFN-T and T-bet. These cells also fail to repress the expression of IL-4 and GATA-3 and retain STAT6 signaling. More importantly, Statl^＋ Th1 ceils can be effectively induced to differentiate into IL-4-producing cells under Th2-inducing conditions. Ectopic expression of T-bet in Statl^＋ Th1 cells dramatically represses their ability to do so and drastically restores IFN-T expression, suggesting that STAT1 may inhibit IL-4 expression through T-bet. Finally, histone H3 acetylation （H3Ac） and histone H3 K4 dimethylation （H3K4dim） were observed in two enhancer regions of II4 gene locus in Statl4- Th1 cells, suggesting a permissive status of I14 gene locus in these cells. Thus, this study reveals new mechanisms by which STAT1 signaling may mediate repression of I14 gene in Th1 cells： upregulating T-bet that subsequently represses GATA3 and IL-4 expression, antagonizing STAT6 signaling, and inhibiting epigenetic modifica

关 键 词：STAT1 Th1/Th2 房间 T 赌注 STAT6 信号 transduction 

分 类 号：N[自然科学总论]