title: Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration.
abstract: Trafficking of myelin-reactive CD4(+) T-cells across the brain endothelium, an essential step in the pathogenesis of multiple sclerosis (MS), is suggested to be an antigen-specific process, yet which cells provide this signal is unknown. Here we provide direct evidence that under inflammatory conditions, brain endothelial cells (BECs) stimulate the migration of myelin-reactive CD4(+) T-cells by acting as non-professional antigen presenting cells through the processing and presentation of myelin-derived antigens in MHC-II. Inflamed BECs internalized myelin, which was routed to endo-lysosomal compartment for processing in a time-dependent manner. Moreover, myelin/MHC-II complexes on inflamed BECs stimulated the trans-endothelial migration of myelin-reactive Th1 and Th17 2D2 cells, while control antigen loaded BECs did not stimulate T-cell migration. Furthermore, blocking the interaction between myelin/MHC-II complexes and myelin-reactive T-cells prevented T-cell transmigration. These results demonstrate that endothelial cells derived from the brain are capable of enhancing antigen-specific T cell recruitment.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Lopes Pinheiro
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Alwin
authors.initials: A
authors.lastname: Kamermans
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Wierts
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: O'Toole
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniël
authors.initials: D
authors.lastname: Boeve
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Verstege
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Susanne Ma
authors.initials: SM
authors.lastname: van der Pol
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvette
authors.identifier: 0000-0001-5997-3665
authors.initials: Y
authors.lastname: van Kooyk
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Wendy Wj
authors.identifier: 0000-0001-9484-261X
authors.initials: WW
authors.lastname: Unger
mesh_terms: D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology*; D001921:Brain / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D004705:Endocytosis; D004727:Endothelium / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D009186:Myelin Sheath / Q000276:immunology*
chemical_list: D000941:Antigens; D000949:Histocompatibility Antigens Class II
keywords: blood-brain barrier; encephalitogenic T cells; human; immunology; mouse; multiple sclerosis; neuroscience