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

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 ⁺CD25 ^high-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.