Identification of IL-17-producing FOXP3+ regulatory T cells in humans (89.1)

Abstract

Abstract IL-17-producing CD4+ T cells (Th17) have recently been defined as a unique subset of pro-inflammatory 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 depends on IL-1β and IL-23. IL-17 was originally found produced by human CD45RO+ memory T cells. We report that human peripheral blood and lymphoid tissue contain a significant number of CD4+FOXP3+ T cells that express CCR6 and produce IL-17 upon activation. These cells co-express FOXP3 and RORγt transcription factors and 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. We further show that human CD4+FOXP3+CCR6- Treg cells differentiate into IL-17 producer cells upon TCR 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 anti-microbial defense while controlling autoimmunity and inflammation. This work was supported by KECK Foundation 01, PP-4 and National Institute of Health Grant AI091130 (to Y.-J.L.)