Intrinsic Requirement for the Vitamin D Receptor in the Development of CD8αα-Expressing T Cells

Vitamin D and vitamin D receptor (VDR) deficiency results in severe symptoms of experimental inflammatory bowel disease in several different models. The intraepithelial lymphocytes of the small intestine contain large numbers of CD8 alpha alpha(+) T cells that have been shown to suppress the immune response to Ags found there. In this study, we determined the role of the VDR in the development of CD8 alpha alpha(+) T cells. There are fewer total numbers of TCR alpha beta(+) T cells in the gut of VDR knockout (KO) mice, and that reduction was largely in the CD8 alpha alpha(+) TCR alpha beta(+) cells. Conversely TCR gamma delta(+) T cells were normal in the VDR KO mice. The thymic precursors of CD8 alpha alpha(+) TCR alpha beta(+) cells (triple-positive for CD4, CD8 alpha alpha, and CD8 alpha beta) were reduced and less mature in VDR KO mice. In addition, VDR KO mice had a higher frequency of the CD8 alpha alpha(+) TCR alpha beta(+) precursors (double-negative [DN] TCR alpha beta(+) T cells) in the gut. The proliferation rates of the DN TCR alpha beta(+) gut T cells were less in the VDR KO compared with those in wild type. Low proliferation of DN TCR alpha beta(+) T cells was a result of the very low expression of the IL-15R in this population of cells in the absence of the VDR. Bone marrow transplantation showed that the defect in VDR KO CD8 alpha alpha(+) TCR alpha beta(+) cells was cell intrinsic. Decreased maturation and proliferation of CD8 alpha alpha(+) TCR alpha beta(+) cells in VDR KO mice results in fewer functional CD8 alpha alpha(+) TCR alpha beta(+) T cells, which likely explains the increased inflammation in the gastrointestinal tract of VDR KO and vitamin D-deficient mice. The Journal of Immunology, 2011, 186: 2819-2825.