Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3

Kentaro Tanaka; Gustavo J Martinez; Xiaowei Yan; Weiwen Long; Kenji Ichiyama; Xinxin Chi; Byung-Seok Kim; Joseph M Reynolds; Yeonseok Chung; Shinya Tanaka; Lan Liao; Yoichi Nakanishi; Akihiko Yoshimura; Pan Zheng; Xiaohu Wang; Qiang Tian; Jianming Xu; Bert W O'Malley; Chen Dong

doi:10.1016/j.celrep.2018.04.088

Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3

Cell Rep. 2018 May 22;23(8):2318-2329. doi: 10.1016/j.celrep.2018.04.088.

Authors

Kentaro Tanaka¹, Gustavo J Martinez², Xiaowei Yan³, Weiwen Long⁴, Kenji Ichiyama¹, Xinxin Chi⁵, Byung-Seok Kim², Joseph M Reynolds², Yeonseok Chung², Shinya Tanaka⁶, Lan Liao⁴, Yoichi Nakanishi⁷, Akihiko Yoshimura⁸, Pan Zheng⁶, Xiaohu Wang⁵, Qiang Tian³, Jianming Xu⁴, Bert W O'Malley⁴, Chen Dong⁹

Affiliations

¹ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 1608582, Japan.
² Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Institute for Systems Biology, Seattle, WA 98109, USA.
⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
⁶ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
⁷ Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan.
⁸ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 1608582, Japan.
⁹ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: chendong@tsinghua.edu.cn.

PMID: 29791844
DOI: 10.1016/j.celrep.2018.04.088

Abstract

T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-β/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORγt-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for RORγt-dependent gene expression in Th17 cell-driven autoimmune diseases.

Keywords: EAE; IL17A; IL1R1; RORγt; p300; pathogenic Th17; steroid receptor coactivator-3.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation*
Cell Polarity
Chromatin / metabolism
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Genetic Loci
HEK293 Cells
Humans
Interleukins / metabolism
Mice, Transgenic
Nuclear Receptor Coactivator 3 / deficiency
Nuclear Receptor Coactivator 3 / metabolism*
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Protein Binding
Receptors, Interleukin-1 / metabolism
Th17 Cells / cytology*
Th17 Cells / immunology*

Substances

Chromatin
Interleukins
Nuclear Receptor Subfamily 1, Group F, Member 3
Receptors, Interleukin-1
Nuclear Receptor Coactivator 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding