In order to perform critical immune functions at sites of inflammation, circulatory T lymphocytes must be able to arrest, adhere, migrate and transmigrate on the endothelial surface. This progression of steps is coordinated by cellular adhesion molecules (CAMs), chemokines, and selectins presented on the endothelium. Two important interactions are between Lymphocyte Function-associated Antigen-1 (LFA-1) and Intracellular Adhesion Molecule-1 (ICAM-1) and also between Very Late Antigen-4 (VLA-4) and Vascular Cell Adhesion Molecule-1 (VCAM-1). Recent studies have shown that T lymphocytes and other cell types can migrate upstream (against the direction) of flow through the binding of LFA-1 to ICAM-1. Since upstream migration of T cells depends on a specific adhesive pathway, we hypothesized that mechanotransduction is critical to migration, and that signals might allow T-cells to remember their direction of migration after the flow is terminated. Cells on ICAM-1 surfaces migrate against the shear flow, but the upstream migration reverts to random migration after the flow is stopped. Cells on VCAM-1 migrate with the direction of flow. However, on surfaces that combine ICAM-1 and VCAM-1, cells crawl upstream at a shear rate of 800 s-1 and continue migrating in the upstream direction for at least 30 minutes after the flow is terminated-we call this 'migrational memory'. Post-flow upstream migration on VCAM-1/ICAM-1 surfaces is reversed upon the inhibition of PI3K, but conserved with cdc42 and Arp2/3 inhibitors. Using an antibody against VLA-4, we can block migrational memory on VCAM-1/ICAM-1 surfaces. Using a soluble ligand for VLA-4 (sVCAM-1), we can promote migrational memory on ICAM-1 surfaces. These results indicate that, while upstream migration under flow requires LFA-1 binding to immobilized ICAM-1, signaling from VLA-4 and PI3K activity is required for the migrational memory of CD4+ T cells. These results indicate that crosstalk between integrins potentiates the signal of upstream migration.

中文翻译：

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整联蛋白串扰允许CD4 + T淋巴细胞在流动后继续沿上游方向迁移。

为了在炎症部位执行关键的免疫功能，循环性T淋巴细胞必须能够在内皮表面上阻滞，粘附，迁移和迁移。步骤的进展由存在于内皮上的细胞粘附分子（CAM），趋化因子和选择素协调。两个重要的相互作用是淋巴细胞功能相关抗原1（LFA-1）和细胞内粘附分子1（ICAM-1）之间以及极晚抗原4（VLA-4）和血管细胞粘附分子1（VCAM）之间的相互作用。 -1）。最近的研究表明，T淋巴细胞和其他细胞类型可以通过LFA-1与ICAM-1的结合而向上游（逆着方向）迁移。由于T细胞的上游迁移取决于特定的粘附途径，因此我们假设机械转导对于迁移至关重要，并且该信号可能允许T细胞在流动终止后记住其迁移方向。ICAM-1表面上的细胞逆着剪切流迁移，但在流停止后，上游迁移恢复为随机迁移。VCAM-1上的细胞沿流动方向迁移。然而，在结合了ICAM-1和VCAM-1的表面上，细胞以800 s-1的剪切速率向上游爬行，并在流动终止后继续沿上游方向迁移至少30分钟，我们称之为“迁移记忆” '。抑制PI3K后，VCAM-1 / ICAM-1表面上的流动后上游迁移被逆转，但与cdc42和Arp2 / 3抑制剂保守。使用针对VLA-4的抗体，我们可以阻止VCAM-1 / ICAM-1表面的迁移记忆。使用VLA-4（sVCAM-1）的可溶性配体，我们可以在ICAM-1表面上促进迁移记忆。这些结果表明，尽管在流动下上游迁移需要LFA-1与固定的ICAM-1结合，但CD4 + T细胞的迁移记忆仍需要来自VLA-4和PI3K活性的信号传导。这些结果表明整联蛋白之间的串扰增强了上游迁移的信号。