title: Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways.
abstract: Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3(1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)2D3-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)2D3, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress.
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Gabriela Bomfim
authors: GB
authors: Ferreira
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: An-Sofie
authors: AS
authors: Vanherwegen
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors: Guy
authors: G
authors: Eelen
authors: Department of Microbial and Molecular Systems, KU Leuven, Leuven 3000, Belgium.
authors: Ana Carolina Fierro
authors: ACF
authors: Gutiérrez
authors: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Leentje
authors: L
authors: Van Lommel
authors: Department of Microbial and Molecular Systems, KU Leuven, Leuven 3000, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent 9000, Belgium; Department of Information Technology, IMinds, Ghent University, Ghent 9000, Belgium.
authors: Kathleen
authors: K
authors: Marchal
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Lieve
authors: L
authors: Verlinden
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Annemieke
authors: A
authors: Verstuyf
authors: Laboratory of Experimental Medicine, Free University of Brussels, Brussels 1050, Belgium.
authors: Tatiane
authors: T
authors: Nogueira
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors: Maria
authors: M
authors: Georgiadou
authors: Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Frans
authors: F
authors: Schuit
authors: Laboratory of Experimental Medicine, Free University of Brussels, Brussels 1050, Belgium.
authors: Décio L
authors: DL
authors: Eizirik
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Conny
authors: C
authors: Gysemans
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium. Electronic address: lut.overbergh@med.kuleuven.be.
authors: Lut
authors: L
authors: Overbergh
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
authors: Chantal
authors: C
authors: Mathieu