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

Abstract

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. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.