Castro Dias, Mariana; Odriozola Quesada, Adolfo; Soldati, Sasha; Bösch, Fabio; Gruber, Isabelle; Hildbrand, Tobias; Sönmez, Derya; Khire, Tejas; Witz, Guillaume; McGrath, James L.; Piontek, Jörg; Kondoh, Masuo; Deutsch, Urban; Zuber, Benoît; Engelhardt, Britta (2021). Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier. Journal of cell science, 134(8) Company of Biologists Limited 10.1242/jcs.253880
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The migration of activated T cells across the blood-brain barrier (BBB) is a critical step in central nervous system (CNS) immune surveillance and inflammation. Whereas T cell diapedesis across the intact BBB seems to occur preferentially through the BBB cellular junctions, impaired BBB integrity during neuroinflammation is accompanied by increased transcellular T cell diapedesis. The underlying mechanisms directing T cells to paracellular versus transcellular sites of diapedesis across the BBB remain to be explored. By combining in vitro live-cell imaging of T cell migration across primary mouse brain microvascular endothelial cells (pMBMECs) under physiological flow with serial block-face scanning electron microscopy (SBF-SEM), we have identified BBB tricellular junctions as novel sites for T cell diapedesis across the BBB. Downregulated expression of tricellular junctional proteins or protein-based targeting of their interactions in pMBMEC monolayers correlated with enhanced transcellular T cell diapedesis, and abluminal presence of chemokines increased T cell diapedesis through tricellular junctions. Our observations assign an entirely novel role to BBB tricellular junctions in regulating T cell entry into the CNS. This article has an associated First Person interview with the first author of the paper.
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