Theodor Kocher Institute, University of Bern, Bern, Switzerland.
Institute of Anatomy, University of Bern, Bern CH-3012, Switzerland.
J Cell Sci. 2021 Apr 15;134(8). doi: 10.1242/jcs.253880. Epub 2021 Apr 26.
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.
激活的 T 细胞穿过血脑屏障（BBB）的迁移是中枢神经系统（CNS）免疫监视和炎症的关键步骤。尽管 T 细胞穿过完整的 BBB 似乎优先通过 BBB 细胞连接发生，但在神经炎症期间 BBB 完整性受损会伴随着跨细胞 T 细胞穿细胞迁移的增加。指导 T 细胞穿过 BBB 进行细胞旁或跨细胞穿细胞迁移的潜在机制仍有待探索。通过将 T 细胞穿过原代小鼠脑微血管内皮细胞（pMBMEC）的体外活细胞迁移与连续块面扫描电子显微镜（SBF-SEM）相结合，我们已经确定 BBB 三细胞连接是 T 细胞穿过 BBB 进行穿细胞迁移的新部位。pMBMEC 单层中三细胞连接蛋白的下调表达或基于蛋白质的相互作用靶向与其增强的跨细胞 T 细胞穿细胞迁移相关，趋化因子的基底外侧存在增加了通过三细胞连接的 T 细胞穿细胞迁移。我们的观察结果赋予 BBB 三细胞连接在调节 T 细胞进入中枢神经系统方面的全新作用。本文有一篇与该论文第一作者的相关第一人称采访。
