DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27

Abstract

During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)(2)D(3), the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis. In contrast, 1,25(OH)(2)D(3) suppressed the gut-homing receptors alpha4beta7 and CCR9. Vitamin D3, the inactive prohormone naturally generated in the skin by exposure to the sun, was processed by dendritic cells and T cells to the active metabolite, providing a mechanism for the local regulation of T cell 'epidermotropism'. Our findings support a model in which dendritic cells process and 'interpret' locally produced metabolites to 'program' T cell homing and microenvironmental positioning.

Vitamin D immunoregulation through dendritic cells

“…Indeed, the canonical nuclear receptors for VD3 and RA, VDR and RARα, often counteract each other's signalling, potentially through competition for their common heterodimeric partner, RXR. Such competition has been documented for T cells: RA induction of integrin α 4 β 7 ‐mediated and CCR9‐mediated intestinal T‐cell homing is antagonized by 1,25‐OH‐VD3 in vitro 67. However, VD3 can also cooperate with RA to induce VitA metabolizing enzymes in human (but not mouse) intestine‐derived or blood‐derived DC subsets,78 whereas it suppresses them in mouse GM‐CSF‐DC 79.…”

“…However, circulating levels of 1,25‐OH‐VD3 in vivo are too low to mediate these effects,8, 66 and 25‐OH‐VD3, the major circulating form of the vitamin, does not itself activate VDR‐dependent transcription. Hence, 1,25‐OH‐VD3 must be generated locally to effect T‐cell programming, and DC can fulfil this function: both in‐vitro ‐derived human moDC and subsets of in vivo DC can generate and present the hormone to T cells 67. At the level of gene expression, all physiological in vivo subsets of mouse DC, including plasmacytoid DC, and both cDC1 and cDC2 express the 25‐hydroxylase Cyp27a1 (Immgen database, http://www.immgen.org/).…”

“…Similarly to macrophages, direct stimulation of human and mouse GM‐CSF‐DC with pathogen‐associated molecular pattern or pro‐inflammatory cytokines triggers Cyp27b1 expression, as does T‐cell contact, especially in a pro‐inflammatory cytokine milieu 23, 69, 70, 71. Moreover, DC isolated from skin‐draining afferent lymph of sheep have also been shown to metabolize VD3 to 1,25‐OH‐VD3 67. Interestingly, human T cells also express Cyp27b1 upon activation and so can carry out the final VD3 conversion step on their own 67.…”

“…T‐cell hyporesponsiveness induction or metabolic switches),23, 32 but these serum 25‐OH‐VD3 levels are too low for the autocrine/paracrine induction of CCR10 on T cells in moDC : T‐cell co‐cultures67 (Fig. 2).…”

“…Such paracrine secretion would therefore influence the tissue‐specific properties of immune instruction. Perhaps skin‐draining DC, which can synthesize 1,25‐OH‐VD3 from D3,67 also transport VD3 after sun exposure, creating a characteristic environment in skin‐draining lymph nodes. This may provide a mechanism to direct skin‐homing T cells to the epidermis in response to sun‐induced damage, where VD3 is high due to UVB‐induced conversion of 7‐dehydro‐cholesterol and subsequent isomerization.…”