title: Postarrest stalling rather than crawling favors CD8(+) over CD4(+) T-cell migration across the blood-brain barrier under flow in vitro.
abstract: Although CD8(+) T cells have been implied in the pathogenesis of multiple sclerosis (MS), the molecular mechanisms mediating CD8(+) T-cell migration across the blood-brain barrier (BBB) into the central nervous system (CNS) are ill defined. Using in vitro live cell imaging, we directly compared the multistep extravasation of activated CD4(+) and CD8(+) T cells across primary mouse brain microvascular endothelial cells (pMBMECs) as a model for the BBB under physiological flow. Significantly higher numbers of CD8(+) than CD4(+) T cells arrested on pMBMECs under noninflammatory and inflammatory conditions. While CD4(+) T cells polarized and crawled prior to their diapedesis, the majority of CD8(+) T cells stalled and readily crossed the pMBMEC monolayer preferentially via a transcellular route. T-cell arrest and crawling were independent of G-protein-coupled receptor signaling. Rather, absence of endothelial ICAM-1 and ICAM-2 abolished increased arrest of CD8(+) over CD4(+) T cells and abrogated T-cell crawling, leading to the efficient reduction of CD4(+) , but to a lesser degree of CD8(+) , T-cell diapedesis across ICAM-1(null) /ICAM-2(-/-) pMBMECs. Thus, cellular and molecular mechanisms mediating the multistep extravasation of activated CD8(+) T cells across the BBB are distinguishable from those involved for CD4(+) T cells.
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Henriette
authors.initials: H
authors.lastname: Rudolph
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Armelle
authors.initials: A
authors.lastname: Klopstein
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gruber
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Blatti
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland. bengel@tki.unibe.ch.
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D015415:Biomarkers; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D036904:Leukocyte Rolling / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057688:Transcellular Cell Migration / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma
keywords: Adhesion; Blood-brain barrier; Crawling; Diapedesis; Stalling; T cells