Vitamin D immunoregulation through dendritic cells

Abstract

Vitamin D (VD3) has been linked to immunological processes, and its supplementation may have a role in treatment or prevention of diseases with underlying autoimmune or pro-inflammatory states. As initiators of the immune responses, dendritic cells (DC) are a potential target of VD3 to dampen autoimmunity and inflammation, but the role of DC in VD3-mediated immunomodulation in vivo is not understood. In addition to being targets of VD3, DC can provide a local source of bioactive VD3 for regulation of T-cell responses. Here we review existing studies that describe the tolerogenic potential of VD3 on DC, and discuss them in the context of current understanding of DC development and function. We speculate on mechanisms that might account for the potent but poorly understood tolerogenic activities of VD3 and the role of DC as both targets and sources of this hormone.

Keywords: dendritic cells; inflammation; vitamin D.

Figure 1

Overview of monocyte‐ and dendritic cell (DC) precursor‐dendritic DC differentiation in vitro and in vivo. Haematopoeitic stem cell‐derived granulocyte–monocyte precursors (GMP) give rise to monocyte‐and‐DC precursors (MDP), after which developmental pathways segregate into a DC lineage with common DC precursors (CDP) and into a monocytic lineage with common monocyte precursors (cMoP). CDP‐derived precursors exhibit early specialization to gut‐tropic mucosal DC precursors (pre‐μDC), regulated by retinoic acid (RA)6, 49 and classical DC precursors (pre‐cDC), and within the latter into cDC1 or cDC2 lineages in the bone marrow.80 Pre‐cDC and pre‐μDC then circulate through blood and home to tissues where they complete their differentiation under tissue‐specific influences.1, 6, 38, 49 The cMoP differentiate to human CD14⁺/mouse Ly6C⁺ monocytes and circulate through blood. Upon migration to tissues, they can fulfil various microenvironmentally specific functions.36 Green boxes delineate populations used for GM‐colony‐stimulating factor (GM‐CSF)‐dependent differentiation protocols in most studies addressing DC–vitamin D3 (VD3) interactions.

Figure 2

Calcitriol (1,25‐OH‐VD3) and dendritic cell (DC) function during different stages of immune activation. Upper panel, left: 1,25‐OH‐VD3 acting on granulocyte–macrophage colony‐stimulating factor (GM‐CSF) ‐differentiating precursors renders DC ‘tolerogenic’ by inhibiting T‐cell stimulation pillars, especially after DC maturation (e.g. performed with tumour necrosis factor‐α or lipopolysaccharide). Also, profound metabolic patterns are induced to promote oxidative phosphorylation and reduce fatty acid synthesis. Middle: 1,25‐OH‐VD3 during DC maturation alters trafficking receptor profiles to redirect migration (see text). Right: Maturation induces DC‐intrinsic up‐regulation of Cyp27b1. Paracrine DC‐derived 1,25‐OH‐VD3 serves as a fourth pillar of DC : T‐cell interaction and promotes regulatory T‐cell generation, inhibits effector T‐cell proliferation and imprints trafficking patterns in instructed T cells. Autocrine 1,25‐OH‐VD3 possibly has effects on DC themselves as well. Lower panel: range of concentrations of VD3 and metabolites in blood and epidermis in vivo and required for immune effects in vitro.