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• W2003678892 abstract "In multiple sclerosis (MS), T cells cross the blood–brain barrier (BBB) and contribute to pathological alterations of cerebral function. Our current insight into the molecular mechanisms involved in immune cell trafficking to the central nervous system (CNS) relies on studies performed with CD4+ T cells in experimental autoimmune encephalomyelitis, an animal model for MS. Still, also CD8+ T cells are involved in MS pathogenesis, as they accumulate within active MS lesions, outnumbering CD4+ T cells. Blocking CNS entry of T cells with the anti-α4-integrin antibody natalizumab has proven efficient in the treatment of relapsing–remitting MS, but is associated with an increased risk of progressive multifocal leukoencephalopathy, suggesting that therapeutic targeting of α4-integrins interferes with CNS immunosurveillance. Using in vitro live cell imaging we directly compared the multi-step migration of CD4+ and CD8+ effector memory T (TEM) lymphocytes across primary mouse brain microvascular endothelial cells (pMBMECs) as a model for the BBB under physiological flow in vitro. To investigate the role of endothelial ICAM-1 and ICAM-2, pMBMECs from ICAM-1null/ICAM-2−/− mice were used in comparison to wild-type pMBMECs. IFNγ/TNFα-stimulated pMBMECs supported shear resistant arrest of CD4+ and CD8+ TEM lymphocytes with CD8+ TEM cells being significantly more efficient than CD4+ TEM in arresting on pMBMECs. Subsequent to arrest, CD4+ TEM cells polarized and crawled before crossing the pMBMECs, whereas CD8+ TEM lymphocytes readily crossed without prior crawling. On ICAM-1null/ICAM-2−/− pMBMECs, we observed a significantly decreased ability of CD4+ and CD8+ TEM cells to arrest with CD8+ TEM cells being significantly more efficient than CD4+ TEM. In the absence of endothelial ICAM-1 and ICAM-2 CD4+ TEM cells failed to crawl and diapedese, whereas 25% of arrested CD8+ TEM cells were able to cross pMBMECs. Our study demonstrates subset-specific mechanisms for CD8+ versus CD4+ TEM cells involved in their multi-step extravasation across the inflamed BBB under physiological flow in vitro. This might offer new targets for efficient blockade of CNS recruitment of destructive immune cells. The in vivo relevance of these findings needs to be further clarified." @default.
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• W2003678892 date "2014-10-01" @default.
• W2003678892 modified "2023-09-26" @default.
• W2003678892 title "Identification of subset specific mechanisms for CD8+ versus CD4+ TEM cells mediating their migration across the inflamed blood–brain barrier under physiological flow in vitro" @default.
• W2003678892 doi "https://doi.org/10.1016/j.jneuroim.2014.08.090" @default.
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