REV-ERBa regulates TH17 cell development and autoimmunity

ROR?t is well recognized as the lineage defining transcription factor for TH17 cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here we demonstrate that the transcriptional repressor REV-ERBa is exclusively expressed in TH17 cells, competes with ROR?t for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as ROR?t-dependent, including Il17a. Deletion of REV-ERBa enhanced TH17-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? modulators, suppressed TH17 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-ERBa negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases. Overall design: 10 samples; 5 conditions with 2 replicates per condition

10

Amir M, Chaudhari S, Wang R, Campbell S, Mosure SA, Chopp LB, Lu Q, Shang J, Pelletier OB, He Y, Doebelin C, Cameron MD, Kojetin DJ, Kamenecka TM, Solt LA