Developmental Vitamin D Deficiency and the Vitamin D Receptor Control Hematopoiesis

Vitamin D status, the vitamin D receptor (VDR), and the ability to produce active vitamin D [1,25(OH)₂D, regulated by Cyp27b1] regulate fetal and adult hematopoiesis. Transgenic reporter mice that express the tdTomato RFP as an indication of Vdr expression were used to identify immune cells that express the Vdr. Vdr/tdTomato⁺ hematopoietic progenitors were identified as early as embryonic day (E)15.5, establishing that these cells have expressed the Vdr and are vitamin D targets. Maternal vitamin D deficiency [D2; serum 25(OH)D < 20 ng/ml] or Vdr knockout or Cyp27b1 knockout resulted in embryos with fewer fetal progenitors. Vdr/tdTomato⁺ expression was found to increase with age in CD8⁺ T cells and innate lymphoid cells (ILCs)1 and ILC3, suggesting that initial Vdr expression in these cells is dependent on environmental factors immediately postbirth. In adult tissues, the frequencies of mature T cells and ILCs as well as Vdr/tdTomato expression were reduced by D2. Maternal D2 resulted in fewer progenitors that expressed Vdr/tdTomato⁺ at E15.5 and fewer Vdr/tdTomato⁺ immune cells in the adult spleen than offspring from D+ mice. We challenged D2 mice with H1N1 influenza infection and found that D2 mice were more susceptible than D+ mice. Treating D2 mice with vitamin D restored Vdr/tdTomato⁺ expression in splenic T cells and partially restored resistance to H1N1 infection, which shows that developmental D2 results in lingering effects on Vdr expression in the adult immune system that compromise the immune response to H1N1 infection. Vitamin D and the Vdr regulate hematopoiesis in both fetal and postnatal phases of immune cell development that impact the immune response to a viral infection.