Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced T <sub>reg</sub> differentiation via up-regulating Nr4a2-Reference-Cited by-同舟云学术

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

Published:2022-06-17 Issue:24 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Zhang Wencan¹^ORCID,Cao Xu²^ORCID,Zhong Xiancai¹^ORCID,Wu Hongmin¹,Feng Mingye²^ORCID,Gwack Yousang³^ORCID,Noah Isakov⁴^ORCID,Sun Zuoming¹^ORCID

Affiliation:

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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