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
Affiliations
Kentaro Tanaka
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
Gustavo J. Martinez
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Xiaowei Yan
Institute for Systems Biology, Seattle, WA 98109, USA
Weiwen Long
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Kenji Ichiyama
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
Xinxin Chi
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
Byung-Seok Kim
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Joseph M. Reynolds
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yeonseok Chung
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Shinya Tanaka
Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA
Lan Liao
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Yoichi Nakanishi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan
Akihiko Yoshimura
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 1608582, Japan
Pan Zheng
Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA
Xiaohu Wang
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
Qiang Tian
Institute for Systems Biology, Seattle, WA 98109, USA
Jianming Xu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Bert W. O’Malley
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Chen Dong
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Corresponding author
Summary: 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. : The unique transcriptional programs in IL-1-induced inflammatory Th17 cells have remained unclear. Tanaka et al. demonstrate that SRC-3 in CD4+ T helper cells functions as a specific coactivator of RORγt, a master transcription factor of Th17 cells, by regulating IL-1-IL1R1 signaling. Keywords: steroid receptor coactivator-3, pathogenic Th17, RORγt, EAE, IL1R1, IL17A, p300
