Mechanisms of Immune Cell Response to Mechanical Load

细胞具有非凡的感知和响应环境机械特性的能力。这种机械传感能力对于个体细胞的运动、细胞分化和命运选择以及发育过程中的大规模组织重排等许多现象都是必不可少的。最近的研究表明，免疫细胞对机械环境有反应，这种机械敏感性调节了它们对感染性物质的反应能力。这个项目的目的是了解由肌动蛋白细丝和肌球蛋白组成的生物聚合物网络产生的内力如何使T淋巴细胞能够调节生化信号，从而利用物理学和工程学的概念和工具加强我们对机械刺激和生化信号在免疫反应中是如何耦合的理解。这项工作对改进人工抗原呈递装置的设计具有潜在的意义，可以提高针对病原体和肿瘤的免疫治疗的效率。PI将开发一门细胞力学的讲座和实验室课程，其中将使用统计和连续介质力学等主题的概念来解释生物过程。国际学生联合会将鼓励该地区的少数民族和高中生参与研究。作为马里兰大学暑期女孩计划的一部分，PI将组织生物物理实验室演示，以鼓励女学生参与科学和技术领域。T细胞受体(TCR)与抗原衍生的多肽结合，形成动态的蛋白质组合，称为信号微簇，是T细胞活化的起始点，也是适应性免疫反应的第一步。最近的研究表明，T细胞对呈现抗原的机械环境有反应，物理力量可以触发T细胞的激活。然而，T细胞结合机械和生化信号以执行特定功能的机制尚不清楚。这个项目将检验这样的假设，即信号微簇对力做出反应，充当动态机械传感器，从而允许细胞做出反应并感觉到抗原承载表面的物理性质。PI的目的是阐明细胞力如何调节激活的T细胞受体上的信号组件的组装(目标1)，确定细胞骨架力和T细胞信号激活(目标2)之间的分子联系，以及这些力如何更全局地导致整个细胞水平的激活(目标3)。这项研究将揭示受体介导的机械环境感知机制的共同原理，以及更普遍研究的整合素介导的机械感知机制。

Cells have the remarkable ability to sense and respond to the mechanical properties of their environment. This mechanosensing ability is essential for many phenomena ranging from the movement of individual cells, cell differentiation and fate choice as well as large-scale tissue rearrangement during development. Recent work has shown that immune cells are responsive to their mechanical environment and this mechanosensitivity tunes their ability to respond to infectious agents. This project aims to understand how internal forces generated by the biopolymer networks of actin filaments and the motor protein, myosin, enable the T lymphocyte to modulate biochemical signaling, enhancing our understanding of how mechanical stimuli and biochemical signaling are coupled during the immune response using concepts and tools from physics and engineering. This work has potential implications for improving the design of artificial antigen-presenting devices that can enhance the efficiency of immunotherapies against pathogens and tumors. The PI will develop a lecture and laboratory course in cell mechanics, in which concepts from topics such as statistical and continuum mechanics will be used to explain biological processes. The PI will encourage minority and high school students from the area to participate in research. The PI will organize biophysics laboratory demonstrations as part of the Summer Girls Program at the University of Maryland to encourage participation of female students in science and technology fields. The binding of T cell receptors (TCRs) to antigen-derived peptides results in the formation of dynamic protein assemblies, called signaling microclusters, that serve as the initiating points for T cell activation and the first step of the adaptive immune response. Recent work has revealed that T cells are responsive to the mechanical environment on which antigens are presented and that physical forces can trigger T cell activation. However, the mechanisms by which T cells combine mechanical and biochemical signals to carry out specific functions is not well understood. This project will test the hypothesis that signaling microclusters are responsive to forces, acting as dynamic mechanosensors, thereby allowing the cell to respond and sense the physical properties of the antigen-bearing surface. The PI aims to elucidate how cellular forces regulate the assembly of signaling assemblies at activated T cell receptors (Aim 1), to determine the molecular linkages between cytoskeletal forces and T cell signaling activation (Aim 2) and how these forces more globally lead to activation at the level of the whole cell (Aim 3). This study will reveal common principles in the mechanisms of receptor-mediated sensing of the mechanical environment and the more commonly studied integrin-mediated mechanosensing.