Cell tension coordinates cellular processes leading to T cell activation

细胞张力协调导致 T 细胞激活的细胞过程

• 批准号: 436846661
• 负责人: Dr. Jeremie Rossy
• 金额: --
• 依托单位: Lehrstuhl Biologie/Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/436846661?language=en
• 关键词: Cell; tension; coordinates; cellular; processes

T cells play a central role in the adaptive immune system, either by orchestrating the response of other immune cells in the case of CD4+ helper and regulatory T cells, or by directly removing infected and cancer cells in the case of cytotoxic CD8+ T cells. When scanning for cognate peptides, T cells are polarized and migrate on various substrates and extracellular environments. Adhesion, actin polymerisation at the leading edge and actomyosin contractions in the uropod generate forces and tension in migrating T cells. Similarly, activation by antigen-presenting cells leads to actin retrograde flow within the lamella at the periphery of the IS and contractions generated by actomyosin arcs at the inner edge of the lamella. Although they are produced by the same cellular machinery, forces in migrating cells and during T cell activation have different kinetics and geometry. Thus, the differences in morphology, polarity and adhesion going along with the transition from migration to activation lead to significant changes in cell tension. Increasing evidence shows that gradients of tension can be maintained in cells. Existence of different tensions at different subcellular localisations means that tension can have a signalling function and orchestrate cellular processes. In fact, among other things, tension has been shown to regulate cell shape and polarity, cytoskeletal organisation, exo/endocytosis and even nuclear events.Hence, the working hypothesis of this research project is that these changes in cell tension induce a mechanical coupling that contributes to organise and coordinate changes in signalling and intracellular trafficking taking place upon TCR engagement of a cognate peptide.Abundant evidence shows that force is a key factor in T cell activation. T cells can sense stiffness and the T cell receptor is a mechanosensor. However, a) mechanobiology experiments on T cells rarely reproduce the actual tensions taking place during T cell activation and b) only a few studies investigate the role played by T cell tension. This project aims at understanding how forces contribute to T cell activation in a physiological context and at uncovering how cell tension orchestrates the cellular processes that underpin T cell activation. To do so, the projects will focus on three objectives: Objective 1: Characterise T cell transition from migration to activation, using a novel assay that we have developed in our research group.Objective 2: Determine how tension contributes to T cell activation, focusing on proteins at the interface between tension and the actin cytoskeleton and by using a cell stretching device.Objective 3: Understand the forces generated by dendritic cells, by measuring these forces using traction force microscopy in presence of T cell co-stimulatory receptors.

T 细胞在适应性免疫系统中发挥着核心作用，无论是在 CD4+ 辅助性 T 细胞和调节性 T 细胞的情况下协调其他免疫细胞的反应，还是在细胞毒性 CD8+ T 细胞的情况下直接清除感染细胞和癌细胞。当扫描同源肽时，T 细胞被极化并在各种基质和细胞外环境上迁移。粘附、前缘肌动蛋白聚合和尾足肌动球蛋白收缩在迁移的 T 细胞中产生力和张力。类似地，抗原呈递细胞的激活导致肌动蛋白在 IS 外围的板层内逆行流动，并由板层内边缘的肌动球蛋白弧产生收缩。尽管它们是由相同的细胞机制产生的，但迁移细胞中和 T 细胞激活过程中的力具有不同的动力学和几何形状。因此，随着从迁移到激活的转变，形态、极性和粘附的差异导致细胞张力的显着变化。越来越多的证据表明，细胞内可以维持张力梯度。不同亚细胞定位存在不同的张力意味着张力可以具有信号传导功能并协调细胞过程。事实上，除其他外，张力已被证明可以调节细胞形状和极性、细胞骨架组织、胞吐/内吞甚至核事件。因此，该研究项目的工作假设是，细胞张力的这些变化诱导机械耦合，有助于组织和协调同源肽的 TCR 接合时发生的信号传导和细胞内运输的变化。大量证据表明力是关键因素 在T细胞激活中。 T 细胞可以感知硬度，T 细胞受体是机械传感器。然而，a) T 细胞的机械生物学实验很少重现 T 细胞激活过程中发生的实际张力，b) 只有少数研究调查 T 细胞张力所起的作用。该项目旨在了解生理环境中力如何促进 T 细胞激活，并揭示细胞张力如何协调支持 T 细胞激活的细胞过程。为此，这些项目将重点关注三个目标： 目标 1：使用我们研究小组开发的一种新颖测定法来表征 T 细胞从迁移到激活的转变。目标 2：确定张力如何促进 T 细胞激活，重点关注张力和肌动蛋白细胞骨架之间界面上的蛋白质，并使用细胞拉伸装置。目标 3：通过使用牵引力测量树突状细胞产生的力，了解这些力 存在 T 细胞共刺激受体的显微镜检查。