Project Summary / Abstract Under homeostatic conditions, TH17 cells have essential roles in protective immunity against extracellular pathogens at mucosal barriers. However, TH17 cells have also been associated with the pathogenesis of several autoimmune diseases, suggesting that failure of TH17 cell homeostasis may give rise to disease states. A significant amount of work has identified key factors that drive TH17 cell development and pathogenicity, including both the nuclear receptors (NRs) RORα and RORγt. However, cell-intrinsic mechanisms that negatively regulate TH17 cell development and associated inflammatory responses have received less attention. Therefore, a more comprehensive understanding of this cell type is needed to better understand TH17 cell biology and autoimmunity in order to identify novel therapeutic targets to treat TH17-mediated diseases. The REV-ERBs (REV-ERBα and REV-ERBβ), two other members of the NR superfamily, are often co-expressed in the same tissues as the RORs and bind the same DNA response elements, which suggest mutual cross talk and co-regulation of their target genes. The REV-ERBs regulate a number of physiological processes and are best known for their roles in the circadian rhythm and metabolic processes. While much is known about the roles for ROR regulation of TH17 cell development and function, the biology of the REV-ERBs in this process is completely unexplored. Our preliminary studies indicate that the REV-ERBs have distinct roles in the regulation of TH17 cell development. Overexpression of the REV-ERBs inhibits TH17 cell development, whereas genetic deletion of each receptor results in increased RORα/γt and CD4+IL-17A expression. Using novel REV-ERB-specific synthetic ligands that we have developed, we demonstrate that pharmacological modulation of REV-ERB activity inhibits TH17 cell development and function both in vitro and in vivo. Based on our data, we hypothesize that the REV-ERBS are key negative regulators of TH17 cell development and function and REV-ERB-specific synthetic ligands may provide novel therapeutics for the treatment of TH17-mediated autoimmune diseases. To test our hypothesis we propose to 1) Identify the roles for the REV-ERB in the regulation of TH17 cell development and function; 2) Demonstrate that the REV-ERBs are negative regulators of TH17 cell development and autoimmune disease progression in vivo; 3) Determine how REV-ERB-specific pharmacological modulation affects REV-ERB activity, TH17 cell functional responses, and autoimmunity. Successful completion of these studies will uncover key roles for the REV-ERBs in TH17 cell biology and reveal that REV-ERB-specific ligands may be a novel therapeutic strategy for the treatment of TH17-mediated autoimmune diseases.