Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

Abstract

Knowledge about the ability of vitamin D to function outside its established role in skeletal homeostasis is not a new phenomenon. Nonclassical immunomodulatory and antiproliferative responses triggered by active 1,25-dihydroxyvitamin D were first reported more than a quarter of a century ago. It is only in recent years, however, that there has been a significant improvement in our understanding of how these nonclassical effects of vitamin D can influence the pathophysiology and possible prevention of human disease. Three particular strands of evidence have been prominent: firstly, population studies have revised our interpretation of normal vitamin D status in humans, suggesting, in turn, that vitamin D insufficiency is a clinical problem of global proportions; secondly, epidemiology has linked vitamin D status with disease susceptibility and/or mortality; and, thirdly, expression of the machinery required to synthesize 1,25-dihydroxyvitamin D in normal human tissue seems to be much more widespread than originally thought. Collectively, these observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis. Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D.

Figure 1

Vitamin D and innate immunity. Activation of macrophage TLR (e.g. TLR2) signaling by pathogens such as as Mycobacterium tuberculosis results in the transcriptional induction of VDR and CP27B expression (blue arrows). Circulating 25OHD (red circles) bound to plasma DBP enters macrophages (red arrows) and is converted to 1,25(OH)₂D (blue circles) by mitochondrial CP27B, and can bind to the VDR in the cell. Once bound to VDR, 1,25(OH)₂D is able to act as a transcriptional factor leading to the induction of cathelicidin expression (solid purple arrow). Incorporation into phagosomes containing internalized pathogen enables cathelicidin to function as an antibacterial agent. As well as upregulating cathelicidin expression, macrophage synthesis of 1,25(OH)₂D can also facilitate negative autoregulation (dashed purple arrows), firstly via increased expression of the feedback enzyme CP24A and its decoy CP24A-SV, and secondly via downregulation of TLR expression. In parallel with autocrine effects on innate antibacterial function, macrophage CP27B might also induce paracrine responses in monocytes, and T or B lymphocytes as a consequence of 1,25(OH)₂D secretion. Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; CP24A, 1,25(OH)₂D 24-hydroxylase; CP24A-SV, 1,25(OH)₂D 24-hydroxylase splice variant; CP27B, 25OHD-1α hydroxylase; DBP, vitamin-D-binding protein; TLR, Toll-like receptor 2; VDR, vitamin D receptor.

Figure 2

Vitamin D, antigen presentation and adaptive immunity. Macrophages and mature DCs can induce both adaptive T-lymphocyte-mediated and B-lymphocyte-mediated immunity by internalizing and processing pathogens. Presentation of the resulting antigens to resting B lymphocytes or resting T lymphocytes leads to the activation of these cells and concomitant adaptive immune response (blue arrows). Macrophages and mature DCs also express the vitamin-D-activating enzyme CP27B and are thus able to synthesize 1,25(OH)₂D from precursor 25OHD (red arrows). The 1,25(OH)₂D synthesized in this way can act in a paracrine fashion on activated B lymphocytes and activated T lymphocytes, which express abundant VDR; local effects of 1,25(OH)₂D are designated by purple arrows. The effects on B and T lymphocyte function are listed. Additional paracrine responses to 1,25(OH)₂D also seem to be manifested via precursor monocytes and immature DCs, which express higher levels of VDR than their mature counterparts. In the case of monocytes, 1,25(OH)₂D seems to stimulate further differentiation of macrophages (purple arrow at the upper left), possibly as an adjunct to the effects of vitamin D on innate immunity (see Figure 1). By contrast, 1,25(OH)₂D suppresses DC maturation (blocked purple arrow at the upper right), providing a mechanism for attenuation of adaptive T lymphocyte responses coupled with enhancement of immunosuppression mediated by T_REG. Abbreviations: 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; CCL22, CC-chemokine ligand 22; CCR10, CC-chemokine receptor 10; CP27B, 25OHD-1α hydroxylase; DC, dendritic cell; Ig, immunoglobulin; T_H1, type 1 T-helper lymphocyte; T_H2, type 2 T-helper lymphocyte; T_REG, T-regulatory lymphocyte; VDR, vitamin D receptor.