Research ArticleT CELL DIFFERENTIATION

The TNFRSF members CD27 and OX40 coordinately limit TH17 differentiation in regulatory T cells

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Science Immunology  21 Dec 2018:
Vol. 3, Issue 30, eaau2042
DOI: 10.1126/sciimmunol.aau2042

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Constraining skin Tregs

Aberrant expression of interleukin-17A (IL-17A) by regulatory T cells (Tregs) is one of the perturbations observed in chronic human inflammatory skin diseases such as psoriasis. Remedios et al. investigated the pathways that normally restrain Tregs from morphing into pathogenic cells secreting IL-17A. Absence of the CD27 and OX40 receptors on skin-resident Tregs in mice led to marked increases in their IL-17A expression and cutaneous inflammation. The subset of cutaneous Tregs making IL-17A in patients with psoriasis and hidradenitis suppurativa expressed low levels of CD27. These studies identify two receptor-ligand pathways that act in concert to maintain the normal homeostatic function of cutaneous Tregs.

Abstract

Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs. Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg 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 Treg plasticity in tissues.

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