Vitamin D-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D synthesis and correlates with increased CD4 T cell CTLA-4 expression.

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D (1,25-(OH)D) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)D synthesis on vitamin D-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)D synthesis was essential for vitamin D-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4 Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)D production and CTLA-4 upregulation in CNS-infiltrating CD4 T cells. We suggest that CTLA-4 serves as a vitamin D-regulated immunological checkpoint in multiple sclerosis prevention.