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

Kentaro Tanaka1, Gustavo J Martinez2, Xiaowei Yan3

  • 1Center 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.

Cell Reports
|May 24, 2018
PubMed

Insights

Steroid receptor coactivator-3 (SRC-3) is essential for pathogenic T helper 17 (Th17) cell differentiation. SRC-3 regulates key genes, impacting autoimmune diseases like experimental autoimmune encephalitis (EAE).

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • T helper 17 (Th17) cells are crucial for immunity and autoimmunity.
  • RORγt is a key transcription factor for Th17 cell development.
  • The role of coactivators in Th17 cell programming remains unclear.

Purpose of the Study:

  • To investigate the role of steroid receptor coactivator-3 (SRC-3) in Th17 cell differentiation.
  • To elucidate the mechanism by which SRC-3 regulates Th17 cell function.
  • To determine SRC-3's involvement in autoimmune disease pathogenesis.

Main Methods:

  • Utilized mouse models with specific T cell deletion of SRC-3.
  • Performed in vitro differentiation assays with various cytokine stimuli.
  • Conducted microarray analysis to identify gene expression changes.
  • Investigated protein-DNA interactions and coactivator recruitment.

Main Results:

  • SRC-3 deletion in T cells reduced experimental autoimmune encephalitis (EAE) incidence and Th17 cell generation in vivo.
  • SRC-3 deficiency impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23 in vitro.
  • SRC-3 regulates the expression of IL-17A and IL-1R1 in a RORγt-dependent manner.
  • SRC-3 is required for p300 acetyltransferase recruitment to target gene loci.

Conclusions:

  • SRC-3 is a critical regulator of pathogenic Th17 cell differentiation.
  • SRC-3 functions as an essential coactivator for RORγt-mediated gene expression.
  • Targeting SRC-3 may offer a therapeutic strategy for Th17 cell-driven autoimmune diseases.
Keywords:
EAEIL17AIL1R1RORγtp300pathogenic Th17steroid receptor coactivator-3

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