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

Immunity
Authors
Keywords
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.

Year of Publication
2014
Journal
Immunity
Volume
40
Issue
4
Pages
477-89
Date Published
2014 Apr 17
ISSN
1097-4180
URL
DOI
10.1016/j.immuni.2014.04.004
PubMed ID
24745332
PubMed Central ID
PMC4066874
Links
Grant list
R01 NS030843 / NS / NINDS NIH HHS / United States
K01 DK090105 / DK / NIDDK NIH HHS / United States
K01DK090105 / DK / NIDDK NIH HHS / United States
DP1OD003958-01 / OD / NIH HHS / United States
P01 NS076410 / NS / NINDS NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
U01 AI102011 / AI / NIAID NIH HHS / United States
R01NS030843, / NS / NINDS NIH HHS / United States
P01NS076410, / NS / NINDS NIH HHS / United States
P01AI039671 / AI / NIAID NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States