1,25-Dihyroxyvitamin D ₃ promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region

FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4 ⁺ T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-β or retinoic acid. 1,25-Dihyroxyvitamin D ₃ [1,25(OH) ₂VD ₃] affects the functions of immune cells including T cells. 1,25(OH) ₂VD ₃ binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH) ₂VD ₃ can promote FOXP3 expression in CD4 ⁺ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH) ₂VD ₃ is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH) ₂VD ₃-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH) ₂VD ₃. Additionally, VD-iTreg cells suppressed the proliferation of target CD4 ⁺ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH) ₂VD ₃ can affect human immune responses by regulating FOXP3 expression in CD4 ⁺ T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells.