title: P-glycoprotein regulates trafficking of CD8(+) T cells to the brain parenchyma.
abstract: The trafficking of cytotoxic CD8(+) T lymphocytes across the lining of the cerebral vasculature is key to the onset of the chronic neuro-inflammatory disorder multiple sclerosis. However, the mechanisms controlling their final transmigration across the brain endothelium remain unknown. Here, we describe that CD8(+) T lymphocyte trafficking into the brain is dependent on the activity of the brain endothelial adenosine triphosphate-binding cassette transporter P-glycoprotein. Silencing P-glycoprotein activity selectively reduced the trafficking of CD8(+) T cells across the brain endothelium in vitro as well as in vivo. In response to formation of the T cell-endothelial synapse, P-glycoprotein was found to regulate secretion of endothelial (C-C motif) ligand 2 (CCL2), a chemokine that mediates CD8(+) T cell migration in vitro. Notably, CCL2 levels were significantly enhanced in microvessels isolated from human multiple sclerosis lesions in comparison with non-neurological controls. Endothelial cell-specific elimination of CCL2 in mice subjected to experimental autoimmune encephalomyelitis also significantly diminished the accumulation of CD8(+) T cells compared to wild-type animals. Collectively, these results highlight a novel (patho)physiological role for P-glycoprotein in CD8(+) T cell trafficking into the central nervous system during neuro-inflammation and illustrate CCL2 secretion as a potential link in this mechanism.
authors.affiliation: Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands, g.kooij@vumc.nl.
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kroon
authors.forename: Debayon
authors.initials: D
authors.lastname: Paul
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: Joost A
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
authors.forename: Liesbeth H P
authors.initials: LH
authors.lastname: Hekking
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Joel S
authors.initials: JS
authors.lastname: Pachter
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018932:Chemokine CCL2; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; C095122:multidrug resistance protein 3