IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases.

Abstract

Abstract Foxp3+ regulatory T cells (Tregs) are a major fraction of T cells in the skin. At steady state, Treg cells make little to no inflammatory cytokines and control against inflammation. However, under certain autoimmune inflammatory settings (including psoriasis) Treg cells have been shown to become dysfunctional, making pro-inflammatory cytokines and contributing to disease pathogenesis. To better understand the role of Treg cells in psoriasis we analyzed the homeostasis and function of these cells in a mouse model of psoriasiform dermatitis (IL-23 mediated skin inflammation). We find that IL-23 induced inflammation drove both proliferation and increased accumulation of Foxp3+T cells in the skin. Furthermore, IL-23 induced a population of Foxp3+T cells that expressed RORgt and made IL17A. The induction of this putative pathogenic population was completely abrogated by a RORgt inverse agonist that inhibits RORgt signaling in vivo. IL-23 was also sufficient to drive the generation of Foxp3+RORgt+IL17A+ cells in vitro, suggesting a cell intrinsic role for IL-23. Interestingly, IL-23 did not induce production of other pro-inflammatory cytokines like IFN-g by Treg cells. This is in line with recent studies where both increased accumulation and the ability of Foxp3+ T cells to make IL17A was reported in lesional skin of psoriasis patients. Current efforts are focused on better defining the characteristics of Foxp3+RORgt+IL17A+ cells in lesional skin of psoriatic patients and mice treated with IL-23. Collectively, our data suggests that IL-23 drives Treg cell plasticity by inducing a population of Foxp3+RORgt+IL17A+ cells that is regulated by RORgt signaling and could be relevant to disease pathogenesis.