Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection
Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection
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DOI：
10.1038/s41467-019-10525-1
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发表时间：
2019-06-13
影响因子：
16.6
通讯作者：
Kawaoka, Shinpei
中科院分区：
文献类型：
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作者：
Hojo, Miki Arai;Masuda, Kyoko;Kawaoka, Shinpei
在胸腺阴性选择过程中，携带对自身MHC/自身肽具有明显强亲和力的T细胞受体（TCR）的自身反应性胸腺细胞被Bim依赖性凋亡去除，但Bim如何被特异性调节以将TCR活化和凋亡诱导联系起来尚不清楚。在这里，我们确定了鼠T细胞特异性基因组增强子E-BAB（（Bubl-Acoxl-Bim）），其缺失导致表达高亲和力TCR的胸腺细胞的积累。一致地，E-BAB敲除小鼠具有缺陷的阴性选择，并且在各种设置中不能删除自身反应性胸腺细胞，这种缺陷伴随着Bim表达减少和凋亡诱导。相比之下，E-BAB通过Bim依赖性途径维持外周T细胞稳态。因此，我们的数据牵连E-BAB作为一个重要的，发育阶段特异性的Bim表达和细胞凋亡诱导的调节剂，以加强胸腺阴性选择和抑制自身免疫。我们的研究揭示了一部分基因组增强子编码，这些编码是TCR信号传导中复杂和背景依赖性基因调控的基础。
During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer E-BAB ((Bubl-Acoxl-Bim)), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, E-BAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, E-BAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate E-BAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.