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Multiple sclerosis (MS). is a demyelinating disease involving genetic and environmental risk factors. Geographic, genetic, and biological evidence suggests that one environmental risk factor may be lack of vitamin D. Here, we investigated how 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). inhibits experimental autoimmune encephalomyelitis (EAE), an MS model. The experiments used adoptive transfer of TCR-transgenic (TCR1) cells specific for myelin basic protein (MBP) peptide into unprimed recipients. When unprimed TCR1 splenocytes were transferred, and the recipients were immunized with peptide, the mock-treated mice developed EAE, but the 1,25-(OH)2D3-treated recipients remained disease-free. Both groups had TCR1 T cells that proliferated in response to MBP Ac1–11 and produced IFN-γ but not IL-4 in the lymph node. In the central nervous system CNS., the mock-treated mice had activated TCR1 T cells that produced IFN-γ but not IL-4, while the 1,25-(OH)2D3-treated mice had TCR1 T cells with a non-activated phenotype that did not produce IFN-γ or IL-4. When activated TCR1 T cells producing IFN-γ were transferred into unprimed mice, the mock-treated and the 1,25-(OH)2D3-treated recipients developed EAE. Likewise, the 1,25-(OH)2D3 did not inhibit Th1 cell IFN-g production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH)2D3 inhibited EAE in MBP-specific TCR-transgenic mice that were Rag-1q, but not in animals that were Rag-1-null. Together, these data refute the hypothesis that the hormone inhibits Th1 cell genesis or function directly or through an action on antigen-presenting cells, or promotes Th2 cell genesis or function. Instead, the evidence supports a model wherein the 1,25-(OH)2D3 acts through a Rag-1-dependent cell to limit the occurrence of activated, autoreactive T cells in the CNS. © 2001 Elsevier Science B.V. All rights reserved.
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