E-protein regulatory network links TCR signaling to effector Treg cell differentiation
E-protein regulatory network links TCR signaling to effector Treg cell differentiation
复制标题
E蛋白调节网络将TCR信号传导与效应Treg细胞分化联系起来
DOI：
10.1073/pnas.1800494116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Zhang, Fuping
中科院分区：
文献类型：
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作者：
Han, Xiaojuan;Huang, Huarong;Zhang, Fuping
效应Treg细胞是Treg细胞群中具有增强调控功能的子集。虽然已知该亚群的诱导和维持依赖于TCR信号传导，但这种信号传导下游的潜在分子机制以及个体TCR依赖基因对效应Treg细胞产生的贡献仍然知之甚少。在本文描述的研究中，E蛋白（E2A/HEB）表达缺失的分化Treg细胞被用来证明E蛋白是与效应Treg细胞分化、定位、功能和增殖相关的大量基因的转录抑制因子。因此，这一发现表明，连续的TCR信号调节e蛋白活性是Treg细胞获得效应功能的主要机制。T细胞抗原受体（TCR）信号传导对于效应调节性T细胞（Treg）的分化和维持至关重要。然而，Treg细胞中单个tcr依赖基因对维持免疫耐受的贡献在很大程度上仍然未知。在这里，我们证明缺乏E蛋白的Treg细胞进一步分化为效应细胞，表现出高表达的效应Treg特征基因，包括IRF4， ICOS, CD103， KLRG-1和rr γt。缺乏E蛋白的Treg细胞表现出更高的稳定性和增强的抑制能力。转录组和ChIP-seq分析显示，E蛋白直接调控了很大比例的效应Treg细胞激活特异性基因，重要的是，E蛋白缺失的Treg细胞中大多数上调基因也是TCR依赖的；这表明E蛋白包含一个关键的基因调控网络，将TCR信号传导与效应Treg细胞分化和功能的控制联系起来。
Significance Effector Treg cells comprise the subset of the Treg cell population that exhibits enhanced regulatory function. Whereas the induction and maintenance of this subset are known to depend on TCR signaling, the underlying molecular mechanisms downstream of such signaling and the contributions of individual TCR-dependent genes to effector Treg cell generation are still poorly understood. In the studies described here differentiated Treg cells in which E-protein (E2A/HEB) expression has been deleted were utilized to demonstrate that E proteins are transcriptional suppressors of a large number of genes associated with effector Treg cell differentiation, localization, function, and proliferation. Thus, this finding indicates that continuous TCR signals modulating E-protein activity is a major mechanism underlying Treg cell acquisition of effector functions. T cell antigen receptor (TCR) signaling is essential for the differentiation and maintenance of effector regulatory T (Treg) cells. However, the contribution of individual TCR-dependent genes in Treg cells to the maintenance of immunotolerance remains largely unknown. Here we demonstrate that Treg cells lacking E protein undergo further differentiation into effector cells that exhibit high expression of effector Treg signature genes, including IRF4, ICOS, CD103, KLRG-1, and RORγt. E protein-deficient Treg cells displayed increased stability and enhanced suppressive capacity. Transcriptome and ChIP-seq analyses revealed that E protein directly regulates a large proportion of the genes that are specific to effector Treg cell activation, and importantly, most of the up-regulated genes in E protein-deficient Treg cells are also TCR dependent; this indicates that E proteins comprise a critical gene regulatory network that links TCR signaling to the control of effector Treg cell differentiation and function.