Kui Shin Voo, Yui-Hsi Wang, Fabio R. Santori, et al.
PNAS, 2009.
IL-17 was originally found produced by circulating human CD45RO+ memory T cells. IL-17–producing CD4+ T helper (Th17) cells have recently been defined as a unique subset of proinflammatory helper cells distinct from the Th1, Th2, and regulatory T (Treg) cells, in terms of developmental regulation and function. Th17 cell differentiation is induced by a combination of IL-6 and TGF-β and is augmented by induction of IL-21, which acts in an autocrine manner. Signaling induced by these cytokines results in phosphorylation of STAT3 and expression of the orphan nuclear receptor RORγt, transcription factors that are required for induction of IL-17 expression. The maintenance, expansion, and further differentiation of the committed Th17 cells depend on IL-1β and IL-23. The differentiation of naive T cells to Th17 cells can be inhibited by IFN-γ, IL-4, IL-27, IL-2, and retinoic acid, molecules critical for the differentiation of naive CD4+ T cells into Th1, Th2, and Treg cell pathways. A recent study found that human Th17 memory cells selectively express high levels of CCR6. In this study, they reported 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 co-express 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. They also found that IL-1β and IL-6 together could induce CCR6−CD4+CD25high Treg to differentiate into IL-17 producer cells in the presence of human serum. The identification of IL-17–producing FOXP3+ Treg cells in both mice and humans suggests that Th17 and FOXP3+ Treg lineages are related in ontogeny. Both lineages appear to depend on TGF-β for their differentiation and/or maintenance, and additional cytokines may determine whether they become Th17, Treg, or dual-function effector T cells. FOXP3+ Treg cells may thus actively contribute to antimicrobial innate immunity by producing IL-17, while they control inflammation and autoimmunity at the same time.