1,25-Dihydroxyvitamin D₃ acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D₃ supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH)₂D₃ inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH)₂D₃ inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio-sensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH)₂D₃ to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH)₂D₃ nor T-cell-specific VDR targeting influenced CD4⁺Foxp3⁺ T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH)₂D₃ acts directly on pathogenic CD4⁺ T cells to inhibit EAE.