分子力学可视化技术研究T细胞机械力信号传导机制

T细胞通过其表面受体，细胞骨架和亚细胞结构不断感知并响应机械力刺激，并利用机械力调控免疫识别和信号传导，然而，这种力学传导机制尚未被阐明。分子力学可视化技术可以将细胞施加在细胞外基质上的机械力转化为荧光信号进行观测，具有pN级别的力学灵敏度和高时、空分辨率。本项目针对目前缺少分子水平上对T细胞在复杂的微环境中力信号传导过程的认识，申请人拟发展、利用多通道的细胞机械力成像方法，研究T细胞在复杂环境中利用机械力调控免疫活化的分子机制。利用分子力学探针的高空间和时间分辨率优势，探究TCR、LFA-1以及CD28等免疫受体的机械力学信号特征以及相互耦合过程、TCR-pMHC键结合动力学特征，以及与T细胞内部生化信号在时、空间上的相关性。这些研究不仅会从分子水平上揭示T细胞复杂的机械力信号传导机制，还将有利于我们从新的角度理解肿瘤免疫系统失调的原因，为开发肿瘤免疫治疗方案提供新的理论和技术指导。

T cells are extremely sensitive to mechanical stimulation and can use mechanical force to regulate immune recognition and signaling. However, the mechanism of this mechano-chemo coupling has not been fully elucidated. Molecular tension fluorescence microscopy (MTFM) can convert the mechanical force exerted by the cell on the extracellular matrix into a fluorescent signal for observation. It has pN-level force sensitivity and high spatial, temporal resolution. This project is aimed to study the mechanism of this mechano-chemo coupling during the T cell activation process using MTFM. .We will develop a multiple channel MTFFM method to study how T cells use pN range force to regulate their immune recognition and functions..Take advantage of the high spatial and temporal resolution of molecular tension image probes, this project will explore the mechanical feature of TCR, LFA-1, and CD28 mediated force, and the crosstalk between these receptors in time and space, and the dynamics of TCR-pMHC bond during cell migration. The project will not only reveal the complex mechanotransduction mechanism of T cells at the molecular level, but also help us to understand the causes of tumor-immune system disorders from a new perspective, and even will provide a new theoretical and technical guidance for the development of tumor immunotherapy.