STAT1 signaling is required for optimal Th1 cell differentiation in mice
STAT1 signaling is required for optimal Th1 cell differentiation in mice
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STAT1 信号传导是小鼠 Th1 细胞最佳分化所必需的
DOI：
10.1007/s11434-010-0030-9
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发表时间：
2010-04-01
影响因子：
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通讯作者：
Huang Zan
中科院分区：
文献类型：
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作者：
Ma Da;Huang Hua;Huang Zan
尽管单独的IFN-γ不会引发I型T辅助细胞（Th 1）分化，但IFN-γ信号传导的丧失会导致Th 1表型受损：IFN-γ受体缺陷型（Ifngr（-/-））Th 1细胞无法永久抑制IL-4表达。它们可以在Th 2诱导条件下分化为产生IL-4的细胞。这些观察结果表明，IFN-γ信号转导在沉默Th 1细胞中的IL 4基因和稳定Th 1表型中起关键作用。IFN-γ信号传导已进一步显示通过抑制STAT 6磷酸化来抑制IL-4表达。本工作旨在研究转导IFN-γ信号的下游分子STAT 1介导抑制Th 1细胞中IL-4表达的机制。结果显示，STAT 1缺陷型幼稚CD 4（+）T细胞表达水平降低的IFN-γ以及水平升高的IL-4。这些细胞在非极化条件下表现出分化为Th 2细胞的倾向。在Th 1诱导条件下，STAT 1缺陷型初始CD 4（+）T细胞显示受损的Th 1分化：Stat 1（-/-）Th 1细胞表达降低水平的IFN-γ和T-bet。这些细胞也不能抑制IL-4和加塔-3的表达并保留STAT 6信号传导。更重要的是，Stat 1（-/-）Th 1细胞可以在Th 2诱导条件下被有效地诱导分化为产生IL-4的细胞。T-bet在Stat 1（-/-）Th 1细胞中的异位表达显著抑制了它们这样做的能力，并显著恢复了IFN-γ的表达，这表明STAT 1可能通过T-bet抑制IL-4的表达。最后，在Stat 1（-/-）Th 1细胞中IL 4基因位点的两个增强子区域观察到组蛋白H3乙酰化（H3（AC））和组蛋白H3 K4二甲基化（H3 K4（dim）），提示IL 4基因位点在这些细胞中处于允许状态。因此，本研究揭示了STAT 1信号转导可能介导IL 4基因在Th 1细胞中的抑制的新机制：上调T-bet，随后抑制GATA 3和IL-4的表达，拮抗STAT 6信号转导，并抑制IL 4基因位点的表观遗传修饰。
Although IFN-gamma alone does not prime type I T helper cell (Th1) differentiation, the loss of IFN-gamma signaling leads to impaired Th1 phenotype: IFN-gamma 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-gamma signaling plays a critical role in silencing Il4 gene in Th1 cells and stabilizing Th1 phenotype. IFN-gamma 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-gamma 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-gamma 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-gamma 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-gamma expression, suggesting that STAT1 may inhibit IL-4 expression through T-bet. Finally, histone H3 acetylation (H3(AC)) and histone H3 K4 dimethylation (H3K4(dim)) 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.