There is emerging evidence that vitamin D status is also linked to the adaptive immune system; see the bot tom half of Figure 1. Both the mature DC and macrophages, as well as the activated B- and T-lymphocytes have the 25(OH)D-1α-hydroxylase and can produce functional amounts of 1α,25(OH)2D3 depending upon the prevailing concentration of the 25(OH)D. Mature dendritic cells (DC) and macrophages are both able to express an adaptive T-lymphocyte- and B-lymphocyte mediated immunity via the process of internalizing and processing the invasive pathogens using cathelicidins. As a consequence, presentation of the resulting anti gens to both resting T-cells and B-cells results in activation of these cells simultaneously by the adaptive immune responses.
Fig1. Schematic organization of the innate and adaptive immune systems and summary of the consequences of the presence of 1α,25(OH)2D3. The top portion lays out the components and responses of the innate immune system in a dendritic cell (DC), and the bottom portion illustrates the complexity of the adaptive immune system in a T-cell. The right-hand column (white boxes) illustrates the biological responses that are stimulated or repressed (green and red arrows) by the actions of 1α,25(OH)2D3 that is produced from 25(OH)D3. The presence of infective pathogens are shown by brown circles. The actions of the toll-like receptors are summarized in Figure 2. TLR, toll-like receptor (black box); DC, dendritic cell; T-cell, T lymphocytes, Mø, macrophage, Treg, regulatory T cell; cyto T-cell, cytotoxic T-cell; Th1, T helper cells. Modified from M. Hewison, Rheum. Dis. Clin. North Am. 38:125 (2012).
Fig2. Activation of a monocyte’s or macrophage’s toll-like signaling receptors by infection by a pathogen like Mycobacterium tuberculosis; involvement of circulating 25(OH)D3, and local 1α,25(OH)2D3 and local VDR. For the innate immune system’s dendritic cells, the key players are toll-like receptors that are single, membrane-spanning receptors that recognize and bind as a ligand structurally conserved molecules only derived from invading microbes. This initiates signal transduction pathways that lead to the suppression or induction of genes that orchestrate the inflammatory response against the invading pathogen. In this figure, a genomic increase in the production of the mitochondrial 25(OH) D3-1α-hydroxylase results in an increased production of 1α,25(OH)2D3. This newly synthesized 1α,25(OH)2D3 binds to the VDR and stimulates the production of cathelicidins that are essential for killing the Mycobacterium tuberculosis pathogen cells. Grey circles, individual invading M. tuberculosis microbes; small grey circles, killed M. tuberculosis microbes; pink triangles, newly synthesized cathelicidin molecules; green circles, 25(OH)D3; red circles, 1α,25(OH)2D3; blue half-moon, 25-hydroxyvitamin D3-1α-hydroxylase; purple icon, the vitamin D receptor (VDR) for 1α,25(OH)2D3. Modified from M. Hewison, Rheum. Dis. Clin. North Am. 38 125 (2012).
