Postarrest stalling rather than crawling favors CD8+ over CD4+ T‐cell migration across the blood–brain barrier under flow in vitro

• Published in: European journal of immunology Vol. 46; no. 9; pp. 2187 - 2203
• Main Authors: Rudolph, Henriette, Klopstein, Armelle, Gruber, Isabelle, Blatti, Claudia, Lyck, Ruth, Engelhardt, Britta
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2016; John Wiley and Sons Inc
• Subjects: Adhesion; Animals; Basic; Biomarkers; Blood-brain barrier; Blood-Brain Barrier - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell adhesion & migration; Cell migration; Central nervous system; Crawling; Diapedesis; Endothelial cells; Endothelial Cells - metabolism; Endothelium, Vascular - metabolism; Extravasation; G protein-coupled receptors; Inflammation; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Leukocyte Rolling - immunology; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Mice, Transgenic; Microvasculature; Molecular modelling; Multiple sclerosis; Neuroimaging; Rodents; Stalling; T cells; Tissue immunology and leukocyte trafficking; Transcellular Cell Migration - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - metabolism; Crawling; Diapedesis; Blood-brain barrier; T cells; Adhesion; Stalling
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201546251

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‐1null/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. Side by side comparing of the multistep extravasation of activated CD4+ and CD8+ T cells across the BBB under flow by in vitro live cell imaging identified subset specific mechanisms of interaction. CD8+ T cells arrested in significantly higher numbers, stalled and crossed the BBB preferentially via the transcellular route.