REV-ERBα Regulates TH17 Cell Development and Autoimmunity

RORγt is well recognized as the lineage-defining transcription factor for T helper 17 (T_H17) cell development. However, the cell-intrinsic mechanisms that negatively regulate T_H17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in T_H17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates T_H17 cell development via repression of genes traditionally characterized as RORγt dependent, including Il17a. Deletion of REV-ERBα enhanced T_H17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed T_H17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBα negatively regulates pro-inflammatory T_H17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of T_H17-mediated autoimmune diseases.