Mechanics of T cell migration

项目摘要/摘要--项目4 迁移是功能免疫系统的重要组成部分。对化学物质和 机械信号提示，细胞需要在复杂的环境中移动，包括内部和之间 纸巾。要做到这一点，细胞需要产生内力，这种内力可以与周围环境相耦合 通过粘连形成基质。这两种物理相互作用必须在时间和空间上微妙地平衡，以 确保机动性。虽然在间充质细胞迁移的背景下已经广泛地探索了这种平衡， 在T细胞和其他免疫细胞使用的阿米巴迁移模式中，这些关系仍然定义不清 细胞。我们的总体目标是定义能够实现和引导免疫细胞迁移的机械相互作用。 刺激突起机械的趋化因子和介导粘连的整合素被认为是 是T细胞迁移的主要生物效应因子。从力学上讲，细胞骨架动力学由肌动蛋白组成 聚合和肌球蛋白收缩是在细胞中产生力量的主要机制。这个 这些成分的相互作用决定了细胞的运动性。我们假设它们的迁徙行为 不同的免疫细胞位于同一连续体中，仅在它们对黏附和 力量的产生。我们进一步推测，效应器编程导致激活的不同 这些物理相互作用的阈值可能会改变不同的效应器子集对其 物理微环境。为了验证这一假设，我们建议进行精确的机械测量 迁移机制并确定它们在体外如何影响T细胞的迁移效率。到时候我们会的 使用我们的体外研究结果作为解释相似的形态行为和相互作用的基础 体内复杂的炎症组织环境。目的1：确定肌动蛋白聚合之间的关系 T细胞的牵拉应力。目标2：确定ECM的组成、组织和材料性能 调节T细胞的黏附。目的3：T细胞的迁移行为是否适应体内的微环境？ 我们的发现将阐明调节T细胞迁移的潜在机械机制，并可用于 为未来的治疗开发新的靶点。

PROJECT SUMMARY/ABSTRACT – PROJECT 4 Migration is an essential component of a functional immune system. Responding to both chemical and mechanical signaling cues, cells need to move in complex environments including both within and between tissues. To accomplish this, cells need to generate internal forces which can be coupled to their surrounding matrix through adhesions. Both of these physical interactions must be delicately balanced in time and space to ensure motility. While this balance has been extensively explored in the context of mesenchymal cell migration, these relationships remain ill-defined in the amoeboid migration modes used by T cells and other immune cells. Our overall goal is to define the mechanical interactions that enable and guide immune cell migration. Chemokines, which stimulate the protrusion machinery, and integrins, which mediate adhesion, are thought to be the primary biological effectors of T cell migration. Mechanically, cytoskeletal dynamics consisting of actin polymerization and myosin contractility are the predominant mechanisms for generating forces in cells. The interplay of these components defines the motility of the cell. We hypothesize that the migration behaviors of different immune cells lie along a single continuum, differing only in their relative contributions of adhesion and force generation. We further speculate that effector programming leads to differences in the activation thresholds for these physical interactions that may modify the way distinct effector subsets respond to their physical microenvironment. To test this hypothesis, we propose to make precise mechanical measurements of the migration machinery and determine how they affect the migration efficiency of T cells in vitro. We will then use our in vitro findings as a basis to interpret similar morphological behaviors and interactions in the more complex in vivo inflamed tissue environment. Aim 1: To determine the relation between actin polymerization and traction stress in T cells. Aim 2: To determine how ECM composition, organization and material properties regulate adhesion in T cells. Aim 3: Do T cells adapt their migration behavior to the microenvironment in vivo? Our findings will elucidate the underlying mechanical mechanisms regulating T cell migration and can be used to develop new targets for future therapies.