Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced Treg differentiation via up-regulating Nr4a2

Wencan Zhang; Xu Cao; Xiancai Zhong; Hongmin Wu; Mingye Feng; Yousang Gwack; Noah Isakov; Zuoming Sun

doi:10.1126/sciadv.abn7662

Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced T_reg differentiation via up-regulating Nr4a2

Sci Adv. 2022 Jun 17;8(24):eabn7662. doi: 10.1126/sciadv.abn7662. Epub 2022 Jun 15.

Authors

Wencan Zhang¹, Xu Cao², Xiancai Zhong¹, Hongmin Wu¹, Mingye Feng², Yousang Gwack³, Noah Isakov⁴, Zuoming Sun¹

Affiliations

¹ Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
² Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
³ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, Immunology and Genetics, Ben-Gurion University of Negev, Bear Sheva, Israel.

Abstract

Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. While SRC1 inhibits the differentiation of regulatory T cells (T_regs) critical for establishing immune tolerance, we show here that SRC2 stimulates T_reg differentiation. SRC2 is dispensable for the development of thymic T_regs, whereas naive CD4⁺ T cells from mice deficient of SRC2 specific in T_regs (SRC2^fl/fl/Foxp3^YFP-Cre) display defective T_reg differentiation. Furthermore, the aged SRC2^fl/fl/Foxp3^YFP-Cre mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4⁺ T cells. SRC2^fl/fl/Foxp3^YFP-Cre mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced T_regs. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of Nr4a2, which then stimulates Foxp3 expression to promote T_reg differentiation. Members of SRC family coactivators thus play distinct roles in T_reg differentiation and are potential drug targets for controlling immune tolerance.

Abstract

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