Identification of IL-17-producing FOXP3+regulatory T cells in humans

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Abstract
IL-17–producing CD4+ T helper (Th17) cells have recently been defined as a unique subset of proinflammatory helper cells whose development depends on signaling initiated by IL-6 and TGF-β, autocrine activity of IL-21, activation of STAT3, and induction of the orphan nuclear receptor RORγt. The maintenance, expansion, and further differentiation of the committed Th17 cells depend on IL-1β and IL-23. IL-17 was originally found produced by circulating human CD45RO+ memory T cells. A recent study found that human Th17 memory cells selectively express high levels of CCR6. In this study, we report that human peripheral blood and lymphoid tissue contain a significant number of CD4+FOXP3+ T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress FOXP3 and RORγt transcription factors. The CD4+FOXP3+CCR6+ IL-17–producing cells strongly inhibit the proliferation of CD4+ responder T cells. CD4+CD25high-derived T-cell clones express FOXP3, RORγt, and IL-17 and maintain their suppressive function via a cell-cell contact mechanism. We further show that human CD4+FOXP3+CCR6− regulatory T (Treg) cells differentiate into IL-17 producer cells upon T-cell receptor stimulation in the presence of IL-1β, IL-2, IL-21, IL-23, and human serum. This, together with the finding that human thymus does not contain IL-17–producing Treg cells, suggests that the IL-17+FOXP3+ Treg cells are generated in the periphery. IL-17–producing Treg cells may play critical roles in antimicrobial defense, while controlling autoimmunity and inflammation.