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。这种机械感知能力对许多现象至关重要，从单个细胞的运动、细胞分化和命运选择，到发育过程中大规模的组织重排。最近的研究表明，免疫细胞对其机械环境有反应，这种机械敏感性调节了它们对感染因子的反应能力。本项目旨在了解肌动蛋白丝和运动蛋白肌球蛋白的生物聚合物网络产生的内力如何使T淋巴细胞调节生化信号，增强我们对机械刺激和生化信号在免疫反应过程中如何耦合的理解，使用物理和工程的概念和工具。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，可以提高免疫治疗对病原体和肿瘤的效率。PI将开发细胞力学的讲座和实验课程，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。PI将鼓励该地区的少数民族和高中生参与研究。PI将组织生物物理实验室演示，作为马里兰大学暑期女生计划的一部分，以鼓励女学生参与科学和技术领域。T细胞受体（TCRs）与抗原衍生肽的结合导致动态蛋白组装的形成，称为信号微簇，作为T细胞激活的起始点和适应性免疫反应的第一步。最近的研究表明，T细胞对抗原呈现的机械环境有反应，并且物理力可以触发T细胞活化。然而，T细胞结合机械和生化信号来执行特定功能的机制尚不清楚。这个项目将测试这样一种假设，即信号微团簇对力有反应，就像动态机械传感器一样，从而允许细胞对携带抗原的表面的物理特性做出反应和感知。该项目旨在阐明细胞力如何调节激活T细胞受体的信号组装（目的1），确定细胞骨架力和T细胞信号激活之间的分子联系（目的2），以及这些力如何更全面地导致整个细胞水平的激活（目的3）。本研究将揭示受体介导的机械环境感知机制和更常见的整合素介导的机械感知机制的共同原理。

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.