Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration
Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration
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DOI：
10.1073/pnas.1701886114
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发表时间：
2017-04-04
影响因子：
11.1
通讯作者：
Jacobelli, Jordan
中科院分区：
文献类型：
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作者：
Estin, Miriam L.;Thompson, Scott B.;Jacobelli, Jordan
血管扩张剂刺激磷酸化蛋白（VASP）和ena -VASP样蛋白（EVL）是细胞骨架效应蛋白，参与调节各种细胞类型的细胞形态、粘附和迁移。然而，这些蛋白在t细胞运动、粘附和体内运输中的作用仍然知之甚少。本研究确定了EVL和VASP在t细胞迁移和运输中的特定作用。我们证明EVL和VASP在活化的t细胞运输中是选择性必需的，但在正常t细胞发育或初始t细胞运输到淋巴结和脾脏中不是必需的。利用多发性硬化症模型，我们发现EVL/ vasp缺陷激活T细胞向实验性自身免疫性脑脊髓炎小鼠炎症中枢神经系统的运输受损。此外，我们发现EVL/VASP双敲除（dKO） T细胞向发炎皮肤和次级淋巴器官的运输存在缺陷。EVL和VASP的缺失导致α 4整合素（CD49d）的表达和功能受损。出乎意料的是，EVL/VASP dKO T细胞在生理剪切力作用下对原代内皮细胞的剪切抗性粘附或爬行能力没有发生改变。相反，EVL和VASP的缺失会损害t细胞的浸润。此外，在α 4整合素阻断后，对照组和EVL/VASP dKO T细胞之间的T细胞浸润变得相当。总的来说，EVL和VASP通过以α 4整合素依赖的方式促进跨内皮迁移的渗透步骤，选择性地介导活化的t细胞运输。
Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naive T-cell trafficking to lymph nodes and spleen. Using amodel of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in alpha 4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon alpha 4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a alpha 4 integrin-dependent manner.