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

Sheng Xiao; Nir Yosef; Jianfei Yang; Yonghui Wang; Ling Zhou; Chen Zhu; Chuan Wu; Erkan Baloglu; Darby Schmidt; Radha Ramesh; Mercedes Lobera; Mark S Sundrud; Pei-Yun Tsai; Zhijun Xiang; Jinsong Wang; Yan Xu; Xichen Lin; Karsten Kretschmer; Peter B Rahl; Richard A Young; Zhong Zhong; David A Hafler; Aviv Regev; Shomir Ghosh; Alexander Marson; Vijay K Kuchroo

doi:10.1016/j.immuni.2014.04.004

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

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

Authors

Sheng Xiao¹, Nir Yosef², Jianfei Yang³, Yonghui Wang⁴, Ling Zhou⁴, Chen Zhu¹, Chuan Wu¹, Erkan Baloglu³, Darby Schmidt³, Radha Ramesh³, Mercedes Lobera³, Mark S Sundrud³, Pei-Yun Tsai⁵, Zhijun Xiang⁴, Jinsong Wang⁴, Yan Xu⁴, Xichen Lin⁴, Karsten Kretschmer⁵, Peter B Rahl⁶, Richard A Young⁷, Zhong Zhong⁴, David A Hafler⁸, Aviv Regev⁹, Shomir Ghosh³, Alexander Marson¹⁰, Vijay K Kuchroo¹¹

Affiliations

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Androstenols / chemistry
Animals
Benzeneacetamides / chemistry
Benzeneacetamides / pharmacology*
Benzhydryl Compounds / chemistry
Benzhydryl Compounds / pharmacology*
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Lineage / drug effects
Cytokines / metabolism
Digoxin / chemistry
Digoxin / pharmacology*
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / immunology
Gene Regulatory Networks / drug effects*
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple Sclerosis / drug therapy*
Multiple Sclerosis / immunology
Myelin-Oligodendrocyte Glycoprotein / immunology
Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Peptide Fragments / immunology
Protein Binding / drug effects
Structure-Activity Relationship
Systems Biology
T-Lymphocyte Subsets / drug effects*
T-Lymphocyte Subsets / immunology
Th17 Cells / drug effects*
Th17 Cells / immunology
Transcription, Genetic / drug effects
Transcriptional Activation / drug effects

Substances

Androstenols
Benzeneacetamides
Benzhydryl Compounds
Cytokines
Heterocyclic Compounds, 4 or More Rings
Myelin-Oligodendrocyte Glycoprotein
Nuclear Receptor Subfamily 1, Group F, Member 3
Peptide Fragments
TMP778
TMP920
myelin oligodendrocyte glycoprotein (34-56)
azastene
Digoxin

Associated data

GEO/GSE56020

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding