title: CD46 Activation Regulates miR-150-Mediated Control of GLUT1 Expression and Cytokine Secretion in Human CD4+ T Cells.
abstract: CD46 is a cell surface complement inhibitor widely expressed in human tissues, in contrast to mice, where expression is limited to the testes. In humans, it has been identified as an important T cell costimulatory receptor, and patients deficient in CD46 or its endogenous ligands are unable to mount effective Th1 T cell responses. Stimulation of human CD4(+) T cells with CD3 and CD46 also leads to the differentiation of a "switched" Th1 population, which shuts down IFN-γ secretion and upregulates IL-10 and is thought to be important for negative feedback regulation of the Th1 response. In the present study, we show that CD46 costimulation leads to amplified microRNA (miR) expression changes in human CD4(+) T cells, with associated increases in activation more potent than those mediated by the "classic" costimulator CD28. Blockade of cell surface CD46 inhibited CD28-mediated costimulation, identifying autocrine CD46 signaling as downstream of CD28. We also identify a downregulation of miR-150 in CD46-costimulated T cells and identify the glucose transporter 1 encoding transcript SLC2A1 as a target of miR-150 regulation, connecting miR-150 with modulation of glucose uptake. We also investigated microRNA expression profiles of CD46-induced switched IL-10-secreting Th1 T cells and found increased expression of miR-150, compared with IFN-γ-secreting Th1 cells. Knockdown of miR-150 led to a reduction in IL-10 but not IFN-γ. CD46 therefore controls both Th1 activation and regulation via a miR-150-dependent mechanism.
authors.affiliation: Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 205-02 Malmö, Sweden;
authors.forename: Ben C
authors.initials: BC
authors.lastname: King
authors.affiliation: Islet Cell Exocytosis Unit, Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, 205-02 Malmö, Sweden; and.
authors.forename: Jonathan L S
authors.identifier: http://orcid.org/0000-0001-8454-6606
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 205-02 Malmö, Sweden;
authors.forename: Ewelina
authors.identifier: http://orcid.org/0000-0002-3062-4020
authors.initials: E
authors.lastname: Golec
authors.affiliation: Islet Cell Exocytosis Unit, Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, 205-02 Malmö, Sweden; and.
authors.forename: Lena
authors.identifier: http://orcid.org/0000-0002-6467-5029
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
authors.affiliation: Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 205-02 Malmö, Sweden; Anna.blom@med.lu.se.
authors.forename: Anna M
authors.identifier: http://orcid.org/0000-0002-1348-1734
authors.initials: AM
authors.lastname: Blom
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis*; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051916:Membrane Cofactor Protein / Q000276:immunology*; D035683:MicroRNAs / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D051272:Glucose Transporter Type 1; D051916:Membrane Cofactor Protein; D035683:MicroRNAs; C497857:CD46 protein, human; C533097:MIR150, human