Genetic and pharmacological inhibition of the nuclear receptor RORα regulates T17 driven inflammatory disorders.

Full development of IL-17 producing CD4 T helper cells (T17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in T17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for T17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased T17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3 T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human T17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming T17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of T17-mediated autoimmunity.