TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses

Abstract

The addition of monophosphoryl lipid A, a minimally toxic derivative of LPS, to nonmucosally administered vaccines induced both systemic and mucosal immune responses to coadministered Ags. This was dependent on an up-regulated expression of 1α-hydroxylase (CYP27B1, 1αOHase), the enzyme that converts 25-hydroxycholecalciferol, a circulating inactive metabolite of vitamin D3, into 1,25(OH)2D3 (calcitriol). In response to locally produced calcitriol, myeloid dendritic cells (DCs) migrated from cutaneous vaccination sites into multiple secondary lymphoid organs, including classical inductive sites of mucosal immunity, where they effectively stimulated B and T cell immune responses. The endogenous production of calcitriol by monophosphoryl lipid A-stimulated DCs appeared to be Toll-IL-1R domain-containing adapter-inducing IFN-β-dependent, mediated through a type 1 IFN-induced expression of 1αOHase. Responsiveness to calcitriol was essential to promote the trafficking of mobilized DCs to nondraining lymphoid organs. Collectively, these studies help to expand our understanding of the physiologically important roles played by locally metabolized vitamin D3 in the initiation and diversification of adaptive immune responses. The influences of locally produced calcitriol on the migration of activated DCs from sites of vaccination/infection into both draining and nondraining lymphoid organs create a condition whereby Ag-responsive B and T cells residing in multiple lymphoid organs are able to simultaneously engage in the induction of adaptive immune responses to peripherally administered Ags as if they were responding to an infection of peripheral or mucosal tissues they were designed to protect.

Topical 1,25‐dihydroxyvitamin D3 subverts the priming ability of draining lymph node dendritic cells

“…In other studies, incorporation of 1,25(OH) 2 D 3 (100 ng) into a subcutaneous vaccine consisting of diphtheria and alum promoted the migration of cutaneous DC to secondary lymphoid sites such as the Peyer's patches. 15 This study details new investigations into the ability of topical 1,25(OH) 2 …”

Vitamin D immunoregulation through dendritic cells

“…However, other studies have reported the expression and metabolic activity of Cyp27b1 in human moDC that subsequently influences T‐cell activity, although the degree to which DC can produce 1,25‐OH‐VD3 in vitro varies with their activation and differentiation status 23, 67, 68, 69. 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.…”

Vitamin D Deficiency in Critically Ill Children

“…Vitamin D is essential for bone health [1][2][3][4] and optimal cardiovascular [5][6][7][8][9][10] and innate immune [11][12][13][14][15] function. Levels of 25-hydroxy vitamin D (25(OH)D) are most often used to assess adequacy of vitamin D stores.…”