Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection.

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.