Kurtz Liz A, Shearer Hope E, Trevail Rosanne, Symeonides Menelaos, Karimi Mobin, Roy Nathan H
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Department of Microbiology & Molecular Genetics, University of Vermont, Burlington, VT 05403, USA.
J Cell Sci. 2025 Jul 15;138(14). doi: 10.1242/jcs.263792. Epub 2025 Jul 18.
T cell migration into inflamed tissue is a key control point in the inflammatory response and relies on integrin interactions with their endothelial ligands. Here, we identify the signaling scaffold CasL (also known as Hef1 and NEDD9) as a central regulator of integrin-dependent migration in primary T cells. We found that CasL is specifically needed for efficient migration on ICAM-1-, but not VCAM-1-coated surfaces. Although wild-type T cells migrating on ICAM-1 formed an actin-rich cell front and move smoothly, T cells lacking CasL instead formed numerous, aberrant membrane blebs. CasL was needed for the normal distribution of F-actin in the cell front and phosphorylated myosin light chain in the cell rear, suggesting that CasL regulates the cytoskeletal architecture in migrating T cells. Importantly, using an in vivo allogeneic hematopoietic transplant model, we found that CasL promotes T cell migration into inflamed peripheral tissue, but was dispensable for trafficking to secondary lymphoid organs. Together, these results indicate CasL functions to control the balance of cytoskeletal components during integrin-dependent migration and highlight the importance of integrin signaling for proper migration into inflamed tissue.
T细胞迁移至炎症组织是炎症反应中的一个关键控制点,且依赖于整合素与其内皮配体的相互作用。在此,我们确定信号支架蛋白CasL(也称为Hef1和NEDD9)是原代T细胞中整合素依赖性迁移的核心调节因子。我们发现,CasL对于在ICAM-1包被的表面上高效迁移是特别必需的,但在VCAM-1包被的表面上则并非如此。虽然在ICAM-1上迁移的野生型T细胞形成了富含肌动蛋白的细胞前沿并能顺利移动,但缺乏CasL的T细胞却形成了大量异常的膜泡。CasL对于F-肌动蛋白在细胞前沿的正常分布以及磷酸化肌球蛋白轻链在细胞后部的正常分布是必需的,这表明CasL调节迁移T细胞中的细胞骨架结构。重要的是,使用体内同种异体造血移植模型,我们发现CasL促进T细胞迁移至炎症外周组织,但对于T细胞转运至次级淋巴器官则并非必需。总之,这些结果表明CasL在整合素依赖性迁移过程中发挥作用以控制细胞骨架成分的平衡,并突出了整合素信号传导对于正确迁移至炎症组织的重要性。