Vitamin D's Effect on Immune Function

Abstract

Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D₃; 1,25-(OH)2D₃) has been ever expanding. In this review, the attention is shifted towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.

Keywords: 1,25-(OH)2D3; Vitamin D; autoimmune disease; immune system; infectious disease; multiple sclerosis; rheumatoid arthritis; type 1 diabetes.

Figure 1

Immunomodulatory actions of active vitamin D (1,25-dihydroxyvitamin D₃; 1,25-(OH)₂D₃). Both the direct as the indirect effects on T-lymphocytes are shown as 1,25-(OH)₂D₃ exerts its effect through direct binding on both the vitamin D receptor of the antigen-presenting cell (APC), in this case the dendritic cell (DC), and the T-lymphocytes directly. The effect of 1,25-(OH)₂D₃ on the APC is both an upregulation of the direct inhibition of the APC, as well as a downregulation of its antigen presentation function. The direct effect of 1,25-(OH)₂D₃ on the T-lymphocytes is a change towards a more tolerogenic state with an induction of Thelper-2 (Th2)-lymphocytes and regulatory T-lymphocytes (Tregs; depicted in green text), together with a downregulation of the pro-inflammatory Thelper-1 (Th1)-lymphocytes, Thelper-17 (Th17)-lymphocytes, and Thelper-9 (Th9)-lymphocytes (depicted in red text). Other abbreviations: IL: interleukin; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; ILT-3: immunoglobulin-like transcript-3; GATA-3: GATA binding protein-3; FoxP3: forkhead box P3, CTLA-4: cytotoxic T lymphocyte associated protein-4.