Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms

• Published in: Immunity (Cambridge, Mass.) Vol. 40; no. 4; pp. 477 - 489
• Main Authors: Xiao, Sheng, Yosef, Nir, Yang, Jianfei, Wang, Yonghui, Zhou, Ling, Zhu, Chen, Wu, Chuan, Baloglu, Erkan, Schmidt, Darby, Ramesh, Radha, Lobera, Mercedes, Sundrud, Mark S., Tsai, Pei-Yun, Xiang, Zhijun, Wang, Jinsong, Xu, Yan, Lin, Xichen, Kretschmer, Karsten, Rahl, Peter B., Young, Richard A., Zhong, Zhong, Hafler, David A., Regev, Aviv, Ghosh, Shomir, Marson, Alexander, Kuchroo, Vijay K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-04-2014
• Subjects: 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
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.04.004

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.
•Three RORγt inhibitors, including an orally bioavailable one, have been identified•RORγt inhibitors are effective in animal models of autoimmunity•Th17 cell genomics is integrated into drug discovery•Chemical inhibitors have distinct effects on RORγt binding