A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-06-26 DOI:10.1126/sciimmunol.adt9239

Connie Shen, Aysha Cerf, Jérémy Postat, Aanya Bhagrath, Mauricio Merino, Angela Mingarelli, Grace Barnes, Dhanesh Patel, Dakota Rogers, Vincent M. Luo, Afnan Abu-Thuraia, Caitlin Schneider, Daniela F. Quail, Abhinav Sharma, Woong-Kyung Suh, Allen Ehrlicher, Jean-François Côté, Judith N. Mandl

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引用次数: 0

Abstract

Immune cells navigate through complex tissue architectures by extensive cellular deformation, low adhesion, and high cell velocities. Loss-of-function mutations in Dedicator of Cytokinesis 8 ( Dock8 ) are associated with immunodeficiency as immune cells becoming entangled during migration through dense environments, but their migration on two-dimensional surfaces remains entirely intact. Here we investigated the specific cytoskeletal defect of Dock8 -deficient activated T cells and describe a central pool of F-actin in wild-type murine and human T cells that is absent in Dock8 knockout T cells. The appearance of the central actin pool is mechanoresponsive and emerges only when cells are very confined. We identified mammalian sterile 20-like (Mst1) as a necessary component in this mechanosensitive pathway in addition to Dock8, allowing for cell shape integrity and survival during migration through complex environments. Our work shows that loss of the central actin pool results in greater nuclear deformation, accrual of DNA damage, and premature cell senescence.

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dock8依赖性的机械敏感的中央肌动蛋白池维持T细胞的形状并在迁移过程中保护细胞核

免疫细胞通过广泛的细胞变形、低粘附和高细胞速度在复杂的组织结构中导航。细胞质分裂献身者8 （Dock8）的功能丧失突变与免疫缺陷有关，因为免疫细胞在密集环境中迁移时会纠缠在一起，但它们在二维表面上的迁移完全保持不变。在这里，我们研究了Dock8缺陷激活T细胞的特异性细胞骨架缺陷，并描述了野生型小鼠和人类T细胞中缺失的f -肌动蛋白中心池。中央肌动蛋白池的出现是机械反应性的，只有在细胞非常受限时才会出现。我们发现除了Dock8外，哺乳动物不育20样蛋白（Mst1）也是这一机械敏感途径的必要组成部分，允许细胞在复杂环境中迁移过程中的形状完整性和存活。我们的工作表明，中央肌动蛋白池的损失导致更大的核变形，DNA损伤的累积和细胞过早衰老。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.