The Effects of 1,25-Dihydroxyvitamin D3 on In Vitro Human NK Cell Development from Hematopoietic Stem Cells

1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] is the biologically active form of vitamin D and is immunoregulatory. 1,25(OH)(2)D-3 binds the vitamin D receptor complex present in many immune populations and can illicit transcriptional responses that vary among different immune subsets. The effects of 1,25(OH)(2)D-3 on mature and developing human NK cells are not well characterized. In the present study, we examined the influence of 1,25(OH)(2)D-3 using an established NK cell differentiation system. Briefly, umbilical cord blood CD34(+) cells were isolated and cultured in conditions optimal for NK cell differentiation, and varying concentrations of 1,25(OH)(2)D-3 were administered. At physiological concentrations (10 nM), 1,25(OH)(2)D-3 impaired NK cell development. Moreover, the NK cells that did develop under the influence of 1,25(OH)(2)D-3 showed a significant reduction in function (cytotoxicity and cytokine production). Conversely, 1,25(OH)(2)D-3 strongly induced hematopoietic stem cells to differentiate along a myeloid pathway, giving rise to CD14(+) cells. Mechanistically, 1,25(OH)(2)D-3 drives hematopoietic progenitor cells to rapidly upregulate monocyte genes (i.e., C/EBP-alpha and CD14). There were no effects of 1,25(OH)(2)D-3 on mature NK cytotoxicity or cytokine production. Collectively, these studies provide novel data showing the negative regulatory effect of 1,25(OH)(2)D-3 on NK cell development.