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

Miki Arai Hojo, Kyoko Masuda, Hiroaki Hojo, Yosuke Nagahata, Keiko Yasuda, Daiya Ohara, Yusuke Takeuchi, Keiji Hirota, Yutaka Suzuki, Hiroshi Kawamoto and Shinpei Kawaoka ()
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Miki Arai Hojo: The University of Tokyo, Kashiwa-shi
Kyoko Masuda: Kyoto University, Kyoto-shi
Hiroaki Hojo: Advanced Telecommunications Research Institute International (ATR), Soraku-gun
Yosuke Nagahata: Kyoto University, Kyoto-shi
Keiko Yasuda: Kyoto University, Kyoto-shi
Daiya Ohara: Kyoto University, Kyoto-shi
Yusuke Takeuchi: Kyoto University, Kyoto-shi
Keiji Hirota: Kyoto University, Kyoto-shi
Yutaka Suzuki: The University of Tokyo, Kashiwa-shi
Hiroshi Kawamoto: Kyoto University, Kyoto-shi
Shinpei Kawaoka: Advanced Telecommunications Research Institute International (ATR), Soraku-gun

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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 EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB 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, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB 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.

Date: 2019
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DOI: 10.1038/s41467-019-10525-1

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