1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (9), p.4210-4220
• Main Authors: Ferreira, Gabriela B, Gysemans, Conny A, Demengeot, Jocelyne, da Cunha, João Paulo M C M, Vanherwegen, An-Sofie, Overbergh, Lut, Van Belle, Tom L, Pauwels, Femke, Verstuyf, Annemieke, Korf, Hannelie, Mathieu, Chantal
• Format: Article
• Language: English
• Subjects: Animals; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - immunology; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Flow Cytometry; Fluorescent Antibody Technique; Immune Tolerance - drug effects; Immune Tolerance - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Phenotype; Real-Time Polymerase Chain Reaction; Vitamin D - analogs & derivatives; Vitamin D - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302350

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.