CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Mucosal Immunity Section, Laboratory of Host Defenses; Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Exp Med. 2014 Dec 15;211(13):2651-68. doi: 10.1084/jem.20132681. Epub 2014 Dec 8.
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.
E 蛋白是 TCR 敏感的转录因子，对于胸腺内 T 细胞的发育至关重要。在这里，我们发现 E 蛋白的缺失会导致外周 TGF-β诱导的调节性 T（iTreg）细胞和胸腺固有调节性 T（nTreg）细胞分化增强。相比之下，Id 蛋白的缺失会导致 nTreg 细胞分化减少。机制分析表明，E 蛋白活性的降低导致了对 Foxp3 表达至关重要的信号通路的去抑制。E 蛋白与 IL-2Rα 增强子位点的结合减少，促进了 TCR 诱导的 IL-2Rα 表达。同样，E 蛋白活性的降低促进了 TCR 诱导的 NF-κB 激活和 c-Rel 的产生。与此一致，微阵列分析表明，尚未表达 Foxp3 的 E 蛋白耗竭细胞表现出 IL-2 和 NF-κB 信号通路的激活，以及与 Foxp3 诱导相关的许多基因的表达增强。最后，使用 Nur77-GFP 小鼠监测 TCR 信号的研究表明，足以诱导 Foxp3 分化的 TCR 信号强度伴随着 E 蛋白水平的下调。综上所述，这些数据表明 TCR 刺激部分通过下调 E 蛋白活性来诱导 Treg 细胞谱系发育。
