Dynamic changes in E-protein activity regulate T reg cell development.
Dynamic changes in E-protein activity regulate T reg cell development.
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E蛋白活性的动态变化调节T reg细胞的发育
DOI：
10.1084/jem.20132681
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Strober W
中科院分区：
文献类型：
--
作者：
Gao P;Han X;Zhang Q;Yang Z;Fuss IJ;Myers TG;Gardina PJ;Zhang F;Strober W
Gao等人表明，E-box蛋白部分通过抑制IL-2 R α表达和IL-2反应性来抑制Foxp 3+调节性T细胞的产生和功能。E蛋白是胸腺内T细胞转换所必需的TCR敏感性转录因子。在这里，我们表明，E蛋白的缺失导致增强的外周TGF-β诱导的调节性T（iT reg）细胞和胸腺自然产生的T reg细胞（nT reg细胞）分化。相反，Id蛋白的缺失导致nT reg细胞分化减少。机制分析表明，降低E-蛋白活性导致Foxp 3表达所必需的信号通路的去抑制。与IL-2 R α增强子位点结合的E蛋白减少促进TCR诱导的IL-2 R α表达。类似地，E蛋白活性降低促进TCR诱导的NF-κB活化和c-Rel的产生。与此一致，微阵列分析表明，E蛋白缺失但尚未表达Foxp 3的细胞表现出IL-2和NF-κB信号通路的激活以及与Foxp 3诱导相关的许多基因的表达增强。最后，使用Nur 77-GFP小鼠监测TCR信号传导的研究表明，足以诱导Foxp 3分化的TCR信号传导强度伴随着E蛋白水平的下调。总的来说，这些数据表明TCR刺激部分地通过下调E蛋白活性来诱导T reg细胞谱系发育。
Gao et al. show that E-box proteins dampen the generation and function of Foxp3+ regulatory T cells in part by inhibiting IL-2Rα expression and IL-2 responsiveness. E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β–induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, deletion of Id proteins results in reduced nT reg cell differentiation. Mechanistic analysis indicated that decreased E-protein activity leads to de-repression of signaling pathways that are essential to Foxp3 expression. Decreased E-protein binding to an IL-2Rα enhancer locus facilitated TCR-induced IL-2Rα expression. Similarly, decreased E-protein activity facilitated TCR-induced NF-κB activation and generation of c-Rel. Consistent with this, microarray analysis indicated that cells with E-protein depletion that are not yet expressing Foxp3 exhibit activation of the IL-2 and NF-κB signaling pathways as well as enhanced expression of many of the genes associated with Foxp3 induction. Finally, studies using Nur77-GFP mice to monitor TCR signaling showed that TCR signaling strength sufficient to induce Foxp3 differentiation is accompanied by down-regulation of E-protein levels. Collectively, these data suggest that TCR stimulation acts in part through down-regulation of E-protein activity to induce T reg cell lineage development.
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