A non-redundant role for RORα in TH17 cell development and TH17-driven inflammatory disorders

Abstract

Abstract Dysregulated TH17 immune responses have been associated with the pathogenesis of several autoimmune diseases. While full development of TH17 cells requires both nuclear receptors RORα and RORγt, most of the work surrounding TH17 cells has focused on the lineage defining transcription factor RORγt. However, TH17 cells are not absent in RORγ−/− mice, suggesting that RORα plays an important role. Despite this, RORα is considered redundant to RORγt and little is known about its function in TH17 cells. The aim of this study was to determine whether RORα played a significant role in TH17 cell development and TH17-driven inflammatory disorders. Using molecular, genetic, and pharmacological approaches our data suggests that RORα has non-redundant functions to RORγt driving TH17 cell development. Loss or overexpression of RORα in CD4+ T cells significantly decreased or increased IL-17A, respectively, despite no change in RORγt expression. Using two mouse models of autoimmunity known to be TH17 driven [experimental autoimmune encephalomyelitis (EAE) and adoptive transfer model of colitis], we found that loss of RORα significantly inhibited the development of EAE and colitis, largely as a consequence of decreased frequencies of pro-inflammatory TH17 cells and increased frequencies of anti-inflammatory Foxp3+ T regulatory cells. Finally, using a RORα-selective small molecule that we developed, we found that modulation of RORα activity significantly inhibited the development of autoimmunity. Our data suggests that RORα plays a non-redundant role to RORγt in TH17 cell development. Studies focusing on assessing RORα activity alone or along with RORγt may lend novel insight into future therapeutic design for TH17-mediated autoimmunity.