Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier

• Published in: Journal of cell science Vol. 134; no. 8
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.04.2021
• Subjects: Collective Cell Migration; SBF-SEM; Diapedesis; Tricellular junctions; T cells; Blood–brain barrier
• ISSN: 0021-9533; 1477-9137; 1477-9137
• DOI: 10.1242/jcs.253880

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.