Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D3 prevention of experimental autoimmune encephalomyelitis

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 D-3 (1,25-(OH)(2)D-3) 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)(2)D-3-treated recipients remained disease-free. Both groups had TCR1 T cells that proliferated in response to MBP Ac1-11 and produced IFN-gamma 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-gamma but not IL-4, while the 1,25(OH)(2)D-3-treated mice had TCR1 T cells with a non-activated phenotype that did not produce IFN-gamma or IL-4. When activated TCR1 T cells producing IFN-gamma were transferred into unprimed mice, the mock-treated and the 1,25-(OH)(2)D-3-treated recipients developed EAE. Likewise, the 1.25-(OH),D3 did not inhibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH),D3 inhibited EAE in MBP-specific TCR-transgenic mice that were Rag-(1+), but not in animals that were Rag-1-null. Together, these data refute the hypothesis that the hormone inhibits Th I 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)(2)D-3 acts through a Rag-1-dependent cell to limit the occurrence of activated., autoreactive T cells in the CNS. (C) 2001 Elsevier Science B.V. All rights reserved.