"Let there be light": the role of vitamin D in the immune response to vaccines

Abstract

Vitamin D's non-skeletal actions, including immunomodulatory role, have been increasingly recognized. Of significance, many immune cells are able to synthesize a biologically active form of vitamin D from circulating 25-hydroxyvitamin D with subsequent intracrine actions, and the vitamin D receptor is broadly distributed. In this review, we discuss vitamin D's potent role in innate and adaptive immune responses and published studies evaluating the impact of serum vitamin D, vitamin D gene pathway polymorphisms or empiric vitamin D supplementation on vaccine immunogenicity. We highlight existing knowledge gaps and propose the steps needed to advance the science and answer the question of whether vitamin D may prove valuable as a vaccine adjuvant for certain vaccines against infectious diseases.

Keywords: adaptive immunity; cellular immunity; immunization; innate immunity; vaccines; vitamin D.

Figure 1

Overview of vitamin D biosynthesis, metabolism, transport to target sites with binding to VDR and transcription related effects, including effects on various immune cells. (1) Sources of vitamin D3 in the body include dietary intake, and biosynthesis in the skin from 7-dehydrocholesterol upon exposure to UVB light (2) Vitamin D3 is transported to the liver where it hydroxylation to 25-(OH)D3 by 25-hydroxylase in the liver via microsomal and mitochondrial enzymes (i.e. CYP2R1, CYP27A1). (3) Circulating 25-(OH) D3 in the kidney then undergoes further hydroxylation by 1-alpha-hydroxylase (CYP27B1) to form the biologically active form of vitamin D, 1,25-(OH)₂D3. (4) Several target cells, including immune cells such as human T lymphocytes, dendritic cells and macrophages, have the capacity for local production of 1,25-(OH)₂ D3 from circulating 25-(OH) D substrate, as these cells also express 1-α-hydroxylase (CYP27B1) when activated by an invading organism. (5) Circulating 1,25-(OH)₂D3 is transported to target cells while bound to D binding protein. Locally produced 1,25-(OH)₂ D3 as well as transported circulating 1,25-(OH)₂D3 then binds to nuclear Vitamin D receptor in target cells. (6) The vitamin D receptor forms a heterodimer with the RXR receptor. VDR regulates gene expression for genes which contain vitamin D response elements, with downstream transcriptional changes. (7) Vitamin D’s effects on dendritic cells includes decreased cell maturation and decreased antigen presentation. (8) There is induction of anti-microbial peptide, cathelicidin production when macrophages are exposed to the active form of vitamin D with increase microbial killing. This is seen specifically in MTB. (9) Vitamin D promotes a shift to a more Th2 phenotype and Treg profile, compared to Th1 and Th17. There is increased production of Th2 mediated cytokines, and reduced IL-2, IFN-γ, TNF-α. This effect on T lymphocytes may either be a direct effect of Vitamin D or indirect via its effects on antigen-presenting cells. (10) Circulating 1,25-(OH)₂ D3 undergoes catabolism to 24-hydroxylated D3 metabolites in the kidney, mediated by CYP24A1.