In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice

J Bone Miner Res. 2001 Nov;16(11):2057-65. doi: 10.1359/jbmr.2001.16.11.2057.


Immune cells carry receptors for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; vitamin D receptor (VDR)] and individuals with severe vitamin D deficiency have immune abnormalities. The aim of this study was to investigate the role of vitamin D in the immune system by studying VDR-knockout (VDR-KO) mice. VDR-KO mice had the same metabolic phenotype as rachitic animals with severe hypocalcemia. Leukocytosis, lymphocyte subset composition in different immune organs, and splenocyte proliferation to several stimuli were normal, except for a lower response to anti-CD3 stimulation (simulation index [SI] of 13 +/- 4 vs. 24 +/- 9 in wild-type mice; p < 0.01). Macrophage chemotaxis was impaired (41 +/- 19% vs. 60 +/- 18% in wild-type mice; p < 0.01) but phagocytosis and killing were normal. In vivo rejection of allogeneic (31 +/- 12 days vs. 45 +/- 26 days of survival in wild-type mice, NS) or xenogeneic (10 +/- 2 days vs. 16 +/- 9 days of survival in wild-type mice, NS) islet grafts was comparable with wild-type mice. Surprisingly, VDR-KO mice were protected from low-dose streptozotocin-induced diabetes mellitus (LDSDM; 5% vs. 65% in wild-type mice; p < 0.001). Correcting hypocalcemia by use of lactose-rich or polyunsaturated fat-rich diets fully restored the immune abnormalities in vitro and the sensitivity to diabetes in vivo. On the other hand, treatment with 1,25(OH)2D3 protected wild-type mice against diabetes but did not protect normocalcemic VDR-KO mice. We conclude that immune defects observed in VDR-KO mice are an indirect consequence of VDR disruption because they can be restored by calcium homeostasis normalization. This study proves that although 1,25(OH)2D3 is a pharmacologic and probably a physiological immunomodulator, its immune function is redundant. Moreover, we confirm the essential role of calcium in the immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Calcifediol / metabolism
  • Calcitriol / metabolism
  • Calcitriol / pharmacology
  • Calcium / metabolism
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / metabolism
  • Humans
  • Hypocalcemia / immunology
  • Hypocalcemia / metabolism
  • In Vitro Techniques
  • Lymphocyte Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, Calcitriol / deficiency
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / immunology*
  • T-Lymphocytes / immunology


  • Adjuvants, Immunologic
  • Receptors, Calcitriol
  • Calcitriol
  • Calcifediol
  • Calcium