1,25-Dihydroxyvitamin D₃ Restrains CD4⁺ T Cell Priming Ability of CD11c⁺ Dendritic Cells by Upregulating Expression of CD31

Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c⁺ bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c⁺ BMDC generated in the presence (VitD-CD11c⁺BMDC) or absence (Veh-CD11c⁺BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c⁺BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c⁺BMDC to prime naïve CD4⁺ T cells in vitro; conversely, increased expression of CD31 on vehicle treated CD11c⁺BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4⁺ T cells during in vitro priming revealed that CD31 reduced the BMDC-T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH)₂D₃ on human CD34⁺ cell-derived CD11c⁺DC, whereby DC generated in the presence of 1,25(OH)₂D₃ had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH)₂D₃ upregulate CD31 expression, resulting in a reduced ability to prime CD4⁺ T cells by impairing a stable cell-cell contact.