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

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

“…Similarly, 1,25-(OH) 2 D 3 -treated Wt male mice had a 7-d delay in EAE onset, 50% reduced EAE incidence, 73% decreased peak severity score, and 90% less cumulative disability than placebo-treated males. These results confirmed our previous results (11,31,32,39).…”

“…However, male and female Wt mice ingesting 1,25-(OH) 2 D 3 had moderate hypercalcemia and weight loss (17 and 25%, respectively). Moderate hypercalcemia and weight loss have not been observed previously at these 1,25-(OH) 2 D 3 doses in Wt mice (32,39,43); we have no explanation as to why they were observed in these experiments. Weight loss (22%) was also observed in female GKO mice ingesting 100 ng/d 1,25-(OH) 2 D 3 ; this was expected because of previous reports of hypercalcemia in Wt mice given this dose (43).…”

“…Vdr transcript abundance was very low in Foxp3-expressing regulatory T cells (Tregs) (11). Because Vdr low-expressing Treg cells are a minority (,1%) of the infiltrating cells and are fewer in GKO mice than Wt mice at EAE stage 3, and most infiltrating cells are Vdr high-expressing Th1 cells, Th17 cells, and macrophages (32,39,46,47), the reduced Vdr expression in GKO mice is unlikely to be explained by the composition of the cellular infiltrate.…”

“…We previously reported that high dietary vitamin D 3 elevated serum 25-hydroxyvitamin D 3 (25-(OH)D 3 ), promoted 1,25-(OH) 2 D 3 synthesis within the CNS, and inhibited EAE induction in female, but not male, mice (29). However, in males and females, administering 1,25-(OH) 2 D 3 inhibited EAE induction and progression, and after disease establishment, induced EAE remission (30)(31)(32). In EAE, we found that 1,25-(OH) 2 D 3 did not inhibit pathogenic CD4 + T cell development or trafficking (32,33), but instead increased the sensitivity of pathogenic T cells to apoptotic signals within the CNS (33,34).…”

“…However, in males and females, administering 1,25-(OH) 2 D 3 inhibited EAE induction and progression, and after disease establishment, induced EAE remission (30)(31)(32). In EAE, we found that 1,25-(OH) 2 D 3 did not inhibit pathogenic CD4 + T cell development or trafficking (32,33), but instead increased the sensitivity of pathogenic T cells to apoptotic signals within the CNS (33,34). These mechanisms required VDR expression in the pathogenic CD4 + T cells (11).…”