ROR{gamma}t Represses IL-10 Production in Th17 Cells To Maintain Their Pathogenicity in Inducing Intestinal Inflammation [IMMUNE REGULATION]

The role of retinoid-related orphan receptor t (RORt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORt-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORt inhibitor–treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1^–/– T cells produced significantly fewer IL-10 when treated with RORt inhibitor compared with wild-type T cells. Furthermore, RORt inhibitor–treated Prdm1^–/– Th17 cells induce more severe colitis compared with RORt inhibitor–treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.

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