Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation.
Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation.
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DOI：
10.1084/jem.20160553
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发表时间：
2017-06-05
期刊：
影响因子：
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通讯作者：
Wang P
中科院分区：
文献类型：
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作者：
Miao T;Symonds ALJ;Singh R;Symonds JD;Ogbe A;Omodho B;Zhu B;Li S;Wang P
Miao等人报道了由Egr 2和3介导的检查点，其通过调节参与增殖和分化的基因来控制T细胞克隆扩增和分化之间的转变，这对于具有有限免疫病理学的最佳免疫应答是必需的。egr 2和egr 3对维持免疫稳态很重要。在这里，我们定义了Egr 2和3的基本功能，作为控制效应T细胞克隆扩增和分化之间过渡的检查点。Egr 2和3缺陷导致克隆扩增缺陷，但T细胞在病毒感染后过度激活和过度分化。相反，持续Egr 2表达增强扩增，但严重损害效应分化。Egr 2结合并控制调节增殖（Myc和Myb）和分化阻遏物（Bcl 6，Id3）的基因的表达，同时阻遏效应子功能所需的转录因子（Zeb2，RORa，RORc和Bhlhe40）。Egr 2和Egr 3在T细胞中的表达受抗原和IFNγ的共同调节，为调节单个T细胞的增殖和分化提供了机制。因此，Egr 2和3是效应CD4和CD8 T细胞的上游调节因子，其对于具有有限免疫病理学的最佳应答是必需的。
Miao et al. report a checkpoint mediated by Egr2 and 3 that controls the transition between T cell clonal expansion and differentiation by regulating genes involved in proliferation and differentiation, which is essential for optimal immune responses with limited immunopathology. Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ, providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology.