Genetic and pharmacological modulation of RORα regulates TH17-driven inflammatory disorders

Abstract While RORγt has been well characterized as the lineage defining transcription factor for TH17 cell development, TH17 cells are not absent in Rorc-deficient mice, suggesting other factors may be required. RORα, a close family member of RORγt, is also expressed during TH17 cell development but is considered functionally redundant, thus little is known about its function in TH17 cells. Using mouse models of autoimmunity and chronic inflammation, we show that expression of RORα is required for TH17 pathogenicity. T-cell specific deletion of RORα significantly abrogated the development of experimental autoimmune encephalomyelitis (EAE) and colitis, due to decreased development of TH17 cells and expression of homing receptors required for cells to gain access to sites of inflammation. These results were accompanied by increased Foxp3+T regulatory cells. Using a RORα-selective small molecule that we developed, we found that modulation of RORα activity largely phenocopied our genetic data, inhibiting the development of EAE, colitis, and relapse in a relapsing remitting model of multiple sclerosis. Importantly, treatment with a RORα modulator did not affect thymic cellularity. Finally, modulation of RORα activity inhibited the development of human TH17 cells and pro-inflammatory cytokine expression from subsets of CD4+CCR6+memory T cells. Our results establish that RORα has non-redundant functions to RORγt driving TH17 cell development and identifies RORα as a potential therapeutic target for the treatment of TH17-mediated autoimmunity.