The TNFRSF members CD27 and OX40 coordinately limit T_H17 differentiation in regulatory T cells.

Regulatory T cells (T_regs) are closely related to T_H17 cells and use aspects of the T_H17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, T_regs express IL-17A, suggesting that dysregulation of T_H17-associated pathways in T_regs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the T_H17 program in T_regs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident T_regs Both CD27 and OX40 signaling suppressed the expression of T_H17-associated genes from T_regs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting T_reg accumulation. T_regs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master T_H17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with T_reg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating T_reg plasticity in tissues.

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