Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D-3 prevention of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a demyelinating disease involving genetic and en vironmental risk factors. Geographic, genetic, and biological evidence sugg ests 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 exper imental autoimmune encephalomyelitis (EAE). an MS model. The experiments us ed adoptive transfer of TCR-transgenic (TCR1) cells specific for myelin bas ic protein (MBP) peptide into unprimed recipients. When unprimed TCR1 splen ocytes were transferred, and the recipients were immunized with peptide. th e mock-treated mice developed EAE, but the 1.25(OH)(2)D-3-treated recipient s 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 nod e. 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 in hibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 pro duction in vitro. Finally, the 1,25-(OH),D3 inhibited EAE in MBP-specific T CR-transgenic mice that were Rag-(1+), but not in animals that were Rag-1-n ull. Together, these data refute the hypothesis that the hormone inhibits T h I cell genesis or function directly or through an action on antigen-prese nting cells, or promotes Th2 cell genesis or function. Instead, the evidenc e supports a model wherein the 1.25-(OH)(2)D-3 acts through a Rag-1-depende nt cell to limit the occurrence of activated., autoreactive T cells in the CNS. (C) 2001 Elsevier Science B.V. All rights reserved.