Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells

The vitamin A metabolite all-trans retinoic acid ( RA) is an important determinant of intestinal immunity. RA primes dendritic cells (DCs) to express CD103 and produce RA themselves, which induces the gut-homing receptors alpha 4 beta 7 and CCR9 on Tcells and amplifies transforming growth factor (TGF)-beta-mediated development of Foxp3(+) regulatory T (Treg) cells. Here we investigated the effect of RA on human DCs and subsequent development of Tcells. We report a novel role of RA in immune regulation by showing that RA-conditioned human DCs did not substantially enhance Foxp3 but induced alpha 4 beta 7(+) CCR9(+) Tcells expressing high levels of interleukin (IL)-10, which were functional suppressive Treg cells. IL-10 production was dependent on DC-derived RA and was maintained when DCs were stimulated with toll-like receptor ligands. Furthermore, the presence of TGF-beta during RA-DC-driven T-cell priming favored the induction of Foxp3(+) Treg cells over IL-10(+) Treg cells. Experiments with naive CD4(+) Tcells stimulated by anti-CD3 and anti-CD28 antibodies in the absence of DCs emphasized that RA induces IL-10 in face of inflammatory mediators. The data thus show for the first time that RA induces IL-10-producing Treg cells and postulates a novel mechanism for IL-10 in maintaining tolerance to the intestinal microbiome.