4.5 Article

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

Journal

JOURNAL OF CELL SCIENCE
Volume 134, Issue 8, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.253880

Keywords

Blood-brain barrier; Tricellular junctions; T cells; Diapedesis; SBF-SEM

Categories

Funding

  1. European Union Seventh Framework Programme (FP7) MC-ITN - Networks for Initial Training nEUROinflammation [607962]
  2. European Union Horizon 2020 Framework Programme MSCA-ITN-ETN - European Training Network BtRAIN [675619]
  3. Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [31003A_170131, 310030_189080, 31003A_179520]
  4. ERA-NET NEURON [32NE30_185536]
  5. Swiss National Science Foundation (SNF) [32NE30_185536, 310030_189080, 31003A_179520, 31003A_170131] Funding Source: Swiss National Science Foundation (SNF)

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The study suggests that tricellular junctions of the BBB serve as novel sites for T cell diapedesis, different from the previously believed cellular junctions. By manipulating the expression of tricellular junctional proteins or targeting chemokines, the ability of T cells to cross the BBB can be enhanced or suppressed.
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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