Immune Imaging Program, The Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.
School of Biomedical Engineering, The University of Sydney, Sydney, NSW, 2006, Australia.
Immunol Cell Biol. 2020 Feb;98(2):93-113. doi: 10.1111/imcb.12304. Epub 2019 Dec 23.
T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin-related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F-actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3-knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon-like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three-dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3-dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities.
T 淋巴细胞利用变形运动在复杂的微环境中有效地进行导航。细胞向前推进所需的肌动蛋白细胞骨架的精确重排是由肌动蛋白调节剂介导的，包括肌动蛋白相关蛋白 2/3（Arp2/3）复合物，这是一种在前沿处引发分支肌动蛋白丝的大分子机器。调节 Arp2/3 活性对肌动球蛋白皮层的生物物理特性和下游 T 细胞功能的影响尚不完全清楚。我们报告说，T 细胞中 Arp3 水平的适度降低会严重影响肌动蛋白皮层的完整性。总 F-肌动蛋白含量的减少导致皮质张力降低和片状伪足形成受损。相反，在 Arp3 敲低细胞中，运动模式主要由出芽迁移主导，其特征是前沿处出现短暂的气球样突起。尽管这种迁移模式似乎与三维环境中的间质迁移兼容，但运动动力学的降低和细胞毒性的损害会干扰 T 细胞的最佳功能。这些发现定义了精细调节的、依赖于 Arp2/3 的机械物理膜完整性在细胞毒性效应 T 淋巴细胞活性中的重要性。
