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Immunity. 2014 Apr 17;40(4):477-89. doi: 10.1016/j.immuni.2014.04.004.

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

Author information

  • 1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 2Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
  • 4GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
  • 5Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
  • 6Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 7Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 8Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
  • 9Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • 10Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: alexander.marson@ucsf.edu.
  • 11Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: vkuchroo@rics.bwh.harvard.edu.

Abstract

We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24745332
[PubMed - indexed for MEDLINE]
PMCID:
PMC4066874
Free PMC Article

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