Abstract
Full development of IL-17 producing CD4+ T helper cells (TH17 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 TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 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 TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.
Highlights
Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt
While RORα has been reported to be expressed in T helper 17 (TH17) cells, we wanted to establish its kinetic expression pattern during TH17 cell development[8]
Data are presented as mean values ± s.e.m
Summary
Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. As a member of the nuclear receptor superfamily, RORα is a ligand-regulated transcription factor and targeting of this receptor in vivo inhibits the development of autoimmunity, it effectively suppresses active inflammation These effects extend to human TH17 cells, both during differentiation and in the regulation of pro-inflammatory cytokine expression in lineage-committed TH17 cell memory subsets. Unlike pharmacologic inhibition of RORγt, we show that RORα inhibition suppresses pro-inflammatory TH17-responses while inducing immunoregulatory function, while leaving thymic T cell development intact These data suggest that RORα is a non-redundant factor that is required for pathogenic TH17 cell function and represents an attractive alternative for treating TH17-associated inflammatory diseases in humans
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