Dendritic cell modulation by 1α,25 dihydroxyvitamin D₃and its analogs: A vitamin D receptor-dependent pathway that promotes a persistent state of immaturityin vitroandin vivo

Abstract

T he dendritic cell (DC) plays a central role in orchestrating cellular immune responses to self and foreign antigens. A process of ''maturation'' that occurs after the acquisition of antigen results in up-regulation of MHC͞peptide and costimulatory ligands on the surface of DCs and in the secretion of immunomodulatory cytokines. In the mature state the DC is primed to activate T cells in an antigen-specific fashion. DC maturation is not, however, a consequence of antigen acquisition per se. Exposure to substances within the tissue microenvironment regulate DC maturational events. Among the factors that induce DC maturation are components of pathogenic microorganisms, products secreted by parenchymal cells and macrophages, and contact with activated T cells (1-6). Whether the preservation of DCs in an immature state results from the absence of maturational stimuli or is also actively maintained is not known.We

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

“…Furthermore, in vitro 1␣25(OH) 2 D 3 inhibits the differentiation and maturation of human monocyte-derived DCs (moDCs), leading to reduced cell surface expression of CD40, CD80, and CD86 costimulatory molecules, reduced allostimulatory function, and decreased survival (5,6). Similar findings are observed in murine bone marrow-derived DCs which have been propagated in the presence of 1␣25(OH) 2 D 3 analogs (7). Indeed, infusion of small numbers of these altered DCs is sufficient to induce tolerance to male Ags in an HY mismatch model (7).…”

1α,25-Dihydroxyvitamin D3 modulates the murine antibody response to pneumococcal capsular polysaccharide serotype 3 through IL-12

“…Interestingly, we have demonstrated no effect on CD40 expression in our system, in analogy to previous reports [16], while in other systems a suppression of this molecule was observed [17,26]. A common feature of all systems is an almost complete suppression of IL-12 secretion by 1a,25(OH) 2 D 3 [18].…”

“…Once thought to exert its effect solely on bone, kidney, and intestine, 1a,25(OH) 2 D 3 has also been shown to play an important role in the modulation of immune function [14,16,17]. 1a,25(OH) 2 D 3 attenuates T lymphocyte mediated disease activity in experimental allergic encephalomyelitis, collagen-induced arthritis, autoimmune thyroiditis, hereditary diabetes, Heyman nephritis, and transplantation rejection [14].…”

“…These effects are believed to be achieved through its action on dendritic cells (DC). 1a,25(OH) 2 D 3 was found to inhibit the IL-12 secretion by DC, and to impair up-regulation of CD80, CD86, CD40, and MHC class II [16][17][18][19].…”

Vitamin D immunoregulation through dendritic cells

“…Using this differentiation protocol, a framework similar to that for human moDC was developed where murine DC are rendered tolerogenic by 1,25‐OH‐VD3 during differentiation. These cells secrete fewer pro‐inflammatory cytokines, express lower levels of co‐stimulatory molecules, and propagate Treg cell conversion and effector T‐cell hyporesponsiveness 47. According to microarray analyses, the above‐mentioned MHC‐II high ‘GM‐DC’ but not MHCII intermediate ‘GM‐Mac’ express VDR,44 so they are probably the subpopulation described as 1,25‐OH‐D3‐responsive.…”