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TLR-Induced Local Metabolism of Vitamin D₃ Plays an Important Role in the Diversification of Adaptive Immune Responses¹

Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132

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 1-hydroxylase (CYP27B1, 1OHase), 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 1OHase. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Department of Pathology and National Institutes of Health Grant AI 059242.

² Address correspondence and reprint requests to Dr. Raymond A. Daynes, Department of Pathology, SOM, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132. E-mail address: ray.daynes{at}path.utah.edu

³ Abbreviations used in this paper: MPLA, monophosphoryl lipid A; 1OHase, 1-hydroxylase; 25(OH)D₃, 25-hydroxycholecalciferol; ALN, axillary lymph node; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; DT, diphtheria CRM 197 protein; LN, lymph node; PLN, popliteal LN; PP, Peyer’s patch; SPL, spleen; TRIF, Toll-IL-1R domain-containing adapter-inducing IFN-β; VDR^–/–, vitamin D₃ receptor; WT, wild type.