title: The effects of 1,25-dihydroxyvitamin D3 on in vitro human NK cell development from hematopoietic stem cells.
abstract: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is the biologically active form of vitamin D and is immunoregulatory. 1,25(OH)2D3 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)2D3 on mature and developing human NK cells are not well characterized. In the present study, we examined the influence of 1,25(OH)2D3 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)2D3 were administered. At physiological concentrations (10 nM), 1,25(OH)2D3 impaired NK cell development. Moreover, the NK cells that did develop under the influence of 1,25(OH)2D3 showed a significant reduction in function (cytotoxicity and cytokine production). Conversely, 1,25(OH)2D3 strongly induced hematopoietic stem cells to differentiate along a myeloid pathway, giving rise to CD14(+) cells. Mechanistically, 1,25(OH)2D3 drives hematopoietic progenitor cells to rapidly upregulate monocyte genes (i.e., C/EBP-α and CD14). There were no effects of 1,25(OH)2D3 on mature NK cytotoxicity or cytokine production. Collectively, these studies provide novel data showing the negative regulatory effect of 1,25(OH)2D3 on NK cell development.
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Weeres
authors.affiliation: Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC 20052; and.
authors.forename: Kim
authors.initials: K
authors.lastname: Robien
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Yong-Oon
authors.initials: YO
authors.lastname: Ahn
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Neulen
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Rachel
authors.initials: R
authors.lastname: Bergerson
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455; Verneris@umn.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology; D018167:Receptors, Calcitriol / Q000276:immunology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D018167:Receptors, Calcitriol; D014815:Vitamins; D002117:Calcitriol