Mechanics of T cell migration

项目总结/摘要-项目4 迁移是功能性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 组织中为了实现这一点，细胞需要产生内力，这些内力可以与周围环境耦合， 基质通过粘连。这两种物理相互作用必须在时间和空间上保持微妙的平衡， 确保运动性。虽然这种平衡已在间充质细胞迁移的背景下得到广泛探讨， 这些关系在T细胞和其他免疫细胞所使用的阿米巴样迁移模式中仍然不明确， 细胞我们的总体目标是定义能够和引导免疫细胞迁移的机械相互作用。 刺激突起机制的趋化因子和介导粘附的整联蛋白被认为 是T细胞迁移的主要生物效应器。从力学上讲，细胞骨架动力学由肌动蛋白 聚合和肌球蛋白收缩性是在细胞中产生力的主要机制。的 这些组分的相互作用决定了细胞的运动性。我们假设， 不同的免疫细胞沿着单一的连续体，不同之处仅在于它们的粘附和 力量生成我们进一步推测，效应器编程导致激活差异 这些物理相互作用的阈值可以改变不同效应子子集响应其 物理微环境为了验证这一假设，我们建议对 迁移机制，并确定它们如何影响T细胞在体外的迁移效率。然后我们将 使用我们的体外研究结果作为基础，解释类似的形态行为和相互作用，在更多的 复杂的体内发炎组织环境。目的1：确定肌动蛋白聚合与细胞凋亡的关系 和T细胞中的牵引应力。目标2：确定ECM成分、组织和材料特性 调节T细胞的粘附。目的3：T细胞的迁移行为是否适应体内的微环境？ 我们的研究结果将阐明调节T细胞迁移的潜在机械机制， 为未来的治疗方法开发新的靶点。

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.