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 CD8αα⁺ 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 CD8αα⁺ T cells. There are fewer total numbers of TCRαβ⁺ T cells in the gut of VDR knockout (KO) mice, and that reduction was largely in the CD8αα ⁺ TCRαβ⁺ cells. Conversely TCRγδ ⁺ T cells were normal in the VDR KO mice. The thymic precursors of CD8αα⁺ TCRαβ⁺ cells (triple-positive for CD4, CD8αα, and CD8αβ) were reduced and less mature in VDR KO mice. In addition, VDR KO mice had a higher frequency of the CD8αα⁺ TCRαβ⁺ precursors (double-negative [DN] TCRαβ⁺ T cells) in the gut. The proliferation rates of the DN TCRαβ⁺ gut T cells were less in the VDR KO compared with those in wild type. Low proliferation of DN TCRαβ⁺ 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 CD8αα⁺ TCRαβ⁺ cells was cell intrinsic. Decreased maturation and proliferation of CD8αα⁺ TCRαβ⁺ cells in VDR KO mice results in fewer functional CD8αα⁺ TCRαβ⁺ T cells, which likely explains the increased inflammation in the gastrointestinal tract of VDR KO and vitamin D-deficient mice.