1,25-Dihydroxyvitamin D3 Promotes Tolerogenic Dendritic Cells with Functional Migratory Properties in NOD Mice

• DOI: 10.4049/jimmunol.1302350
• Publication Date: 2014-03-25T05:39:59Z
• Authors: Gabriela B Ferreira; Conny A Gysemans; Jocelyne Demengeot; João Paulo M C M ...; An-Sofie Vanherwegen; Lut Overbergh; Tom L Van Belle; Femke Pauwels; Annemieke Verstuyf; Hannelie Korf; Chantal Mathieu
• Keywords: Fluorescent Antibody Technique; Mice, Transgenic; Dendritic Cells; Flow Cytometry; Lymphocyte Activation; Real-Time Polymerase Chain Reaction; 3. Good health; Mice, Inbred C57BL; Chemotaxis, Leukocyte; Mice; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Mice, Inbred NOD; Immune Tolerance; Animals; Vitamin D

Abstract The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is able to promote the generation of tolerogenic mature dendritic cells (mDCs) with an impaired ability to activate autoreactive T cells. These cells could represent a reliable tool for the promotion or restoration of Ag-specific tolerance through vaccination strategies, for example in type 1 diabetes patients. However, successful transfer of 1,25(OH)2D3-treated mDCs (1,25D3-mDCs) depends on the capacity of 1,25(OH)2D3 to imprint a similar tolerogenic profile in cells derived from diabetes-prone donors as from diabetes-resistant donors. In this study, we examined the impact of 1,25(OH)2D3 on the function and phenotype of mDCs originating from healthy (C57BL/6) and diabetes-prone (NOD) mice. We show that 1,25(OH)2D3 is able to imprint a phenotypic tolerogenic profile on DCs derived from both mouse strains. Both NOD- and C57BL/6-derived 1,25D3-mDCs decreased the proliferation and activation of autoreactive T cells in vitro, despite strain differences in the regulation of cytokine/chemokine expression. In addition, 1,25D3-mDCs from diabetes-prone mice expanded CD25+Foxp3+ regulatory T cells and induced intracellular IL-10 production by T cells in vitro. Furthermore, 1,25D3-mDCs exhibited an intact functional migratory capacity in vivo that favors homing to the liver and pancreas of adult NOD mice. More importantly, when cotransferred with activated CD4+ T cells into NOD.SCID recipients, 1,25D3-mDCs potently dampened the proliferation of autoreactive donor T cells in the pancreatic draining lymph nodes. Altogether, these results argue for the potential of 1,25D3-mDCs to restore Ag-specific immune tolerance and arrest autoimmune disease progression in vivo.