title: 1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice.
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.
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Ferreira
authors.forename: Conny A
authors.initials: CA
authors.lastname: Gysemans
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Demengeot
authors.forename: João Paulo M C M
authors.initials: JP
authors.lastname: da Cunha
authors.forename: An-Sofie
authors.initials: AS
authors.lastname: Vanherwegen
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.forename: Tom L
authors.initials: TL
authors.lastname: Van Belle
authors.forename: Femke
authors.initials: F
authors.lastname: Pauwels
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C118756:dihydroxy-vitamin D3; D014807:Vitamin D