REV-ERBα Regulates TH17 Cell Development and Autoimmunity

ROR gamma t is well recognized as the lineage-defining transcription factor for T helper 17 (T(H)17) cell development. However, the cell-intrinsic mechanisms that negatively regulate T(H)17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERB alpha is exclusively expressed in T(H)17 cells, competes with ROR gamma t for their shared DNA consensus sequence, and negatively regulates T(H)17 cell development via repression of genes traditionally characterized as ROR gamma t dependent, including parallel to 17a. Deletion of REV-ERB alpha enhanced T(H)17-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 ROR gamma modulators, suppressed T(H)17 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-ERB alpha negatively regulates pro-inflammatory T(H)17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of T(H)17-mediated autoimmune diseases.