STAT1 signaling is required for optimal Thl cell differentiation in mice

• 来源期刊: 科学通报(英文版)
• 学科: 地球科学
• 年，卷（期）: 2010,（11）
• 所属期刊栏目: Immunology
• 页码范围: 1032-1040
• 页数: 9页
• 分类号: N
• 语种: 英文

摘要

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 modifications in 114 gene locus.