Lineage-specific Effects of 1,25-Dihydroxyvitamin D3 on the Development of Effector CD4 T Cells

Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1 alpha,25-dihydroxyvitamin D-3 (1,25-D-3), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D-3 compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells. Relative to Th17 and Th9 cells, the effects of 1,25-D-3 on Th1 cells were modest, reflecting the significantly reduced levels of the receptor for vitamin D in this lineage. The use of cells deficient in IL-10 or antibodies that block IL-10 signaling abolished the inhibitory effect of 1,25-D-3 on Th9 cells but had no effect on inhibition of Th17 cell frequencies. Thus, the induction of IL-10 in cultures of Th9 cells is an important mechanism by which 1,25-D-3 compromises Th9 development but does not explain inhibition of Th17 cells. A survey of select representatives of the Th17 transcriptome revealed that the levels of mRNA that encode ROR gamma t, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D-3, whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged. These data suggest that vitamin D deficiency may promote autoimmunity by favoring the inordinate production of Th17 and Th9 cells at the expense of regulatory IL-10-producing T cells.