In:
Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-06-13)
Abstract:
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 ( Bub1 - 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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-019-10525-1
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2553671-0
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