title: Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.
abstract: 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)(2)D(3) did not inhibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH)(2)D(3) 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 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)(2)D(3) acts through a Rag-1-dependent cell to limit the occurrence of activated, autoreactive T cells in the CNS.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison 53706, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Nashold
authors.forename: K A
authors.initials: KA
authors.lastname: Hoag
authors.forename: J
authors.initials: J
authors.lastname: Goverman
authors.forename: C E
authors.initials: CE
authors.lastname: Hayes
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic; D018167:Receptors, Calcitriol / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; C064658:RAG-1 protein; D002117:Calcitriol