Vitamin A Metabolites Induce Gut-Homing FoxP3+ Regulatory T Cells

Abstract

In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3- CD4+ T cells into a unique FoxP3+ regulatory T cell subset (termed "retinoid-induced FoxP3+ T cells") in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid induces histone acetylation at the FoxP3 gene promoter and expression of the FoxP3 protein in CD4+ T cells. The induction of retinoid-induced FoxP3+ T cells is mediated by the nuclear retinoic acid receptor alpha and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-beta1-dependent generation of FoxP3+ regulatory T cells but decrease the TGF-beta1- and IL-6-dependent generation of inflammatory Th17 cells in mouse T cells. Retinoid-induced FoxP3+ T cells can efficiently suppress target cells and, thus, have a regulatory function typical for FoxP3+ T cells. A unique cellular feature of these regulatory T cells is their high expression of gut-homing receptors that are important for migration to the mucosal tissues particularly the small intestine. Taken together, these results identify retinoids as positive regulatory factors for generation of gut-homing FoxP3+ T cells.