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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)2318-2329
Number of pages12
JournalCell Reports
Volume23
Issue number8
DOIs
Publication statusPublished - 2018 May 22

Keywords

  • EAE
  • IL17A
  • IL1R1
  • RORγt
  • p300
  • pathogenic Th17
  • steroid receptor coactivator-3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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