Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells

Background The vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression is priming of dendritic cells (DCs) to induce regulatory T (Treg) cells. Objective Currently, there is confusion about the phenotype of VitD3-induced Treg cells and the DC-derived molecules driving their development. We investigated Treg cell induction after VitD3 priming of 2 distinct skin DC subsets: Langerhans cells (LCs) and dermal dendritic cells (DDCs). Methods LCs and DDCs primed with VitD3 were cocultured with allogeneic naive T cells. The phenotype and function of the DCs and induced T cells were analyzed. Results Both VitD3-primed DC subtypes induced T cells with regulatory activity. Unexpectedly, whereas the Treg cell populations generated by VitD3-primed LCs were CD25 hi CD127 lo forkhead box protein 3 (Foxp3)–positive cells, which meet the criteria of classical inducible Treg cells, the T cells developing in response to VitD3-primed DDCs were Foxp3 − T R 1 cells expressing IL-10. Inhibition experiments revealed that LC-derived TGF-β is a key factor in the induction of Foxp3 + Treg cells, whereas DDC-derived IL-10 is important for the induction of IL-10 + T R 1 cells. Conclusion Thus we report the novel finding that distinct but closely related DC subsets are differentially programmed by VitD3 to support development of either TGF-β–dependent Foxp3 + Treg cells or IL-10–dependent IL-10 + Treg cells.