Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling

Abstract

Multiple pathways converge to result in the overexpression of T_h17 cells in the absence of either vitamin D or the vitamin D receptor (VDR). CD4⁺ T cells from VDR knockout (KO) mice have a more activated phenotype than their wild-type (WT) counterparts and readily develop into T_h17 cells under a variety of in vitro conditions. Vitamin D-deficient CD4⁺ T cells also overproduced IL-17 in vitro and 1,25 dihydroxyvitamin D₃ inhibited the development of T_h17 cells in CD4⁺ T-cell cultures. Conversely, the induction of inducible (i) Tregs was lower in VDR KO CD4⁺ T cells than WT and the VDR KO iTregs were refractory to IL-6 inhibition. Host-specific effects of the VDR were evident on in vivo development of naive T cells. Development of naive WT CD4⁺ T cells in the VDR KO host resulted in the overexpression of IL-17 and more severe experimental inflammatory bowel disease (IBD). The increased expression of T_h17 cells in the VDR KO mice was associated with a reduction in tolerogenic CD103⁺ dendritic cells. The data collectively demonstrate that T_h17 and iTreg cells are direct and indirect targets of vitamin D. The increased propensity for development of T_h17 cells in the VDR KO host results in more severe IBD.