Functional consequences on T cell activation of mechanical input delivered by antigen-presenting cells

抗原呈递细胞传递的机械输入对 T 细胞激活的功能影响

• 批准号: 520916856
• 负责人: Dr. Jeremie Rossy
• 金额: --
• 依托单位: School of Physics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/520916856?language=en
• 关键词: Functional; consequences; cell; activation; mechanical

T lymphocytes, or T cells, play a central role in mounting an adaptive immune response because of their ability to produce a reaction tailored to the type and context of the inflammation, whether it be an infection or a developing tumour. This ability is related to the specific nature of the T cell activation process, which is achieved through a highly specialised interface with antigen-presenting cells, the immunological synapse. Antigen-presenting cells activate and instruct T cells through a dedicated ligand-receptor system at the synapse. In a recent project, we have uncovered that dendrtic cells, which are professional antigen-presenting cells, additionally deliver a mechanical signal to T cell through the immunological synapse. The key objectives of the proposed project are to understand how a mechanical input, such as the one generated by dendritic cells, can impact on the mechanisms and outcome of T cell activation. To do so, we will use a validated cell stretcher, which can generate a stress pattern similar to the forces produced by dendritic cells at the synapse. In a first objective, we will determine how external forces can regulate key processes and signalling pathways related to T cell activation, using the stretcher in combination with fluorescent reporters in live cells microscopy. In a second objective, we will change scale and adopt a multiomics approach based on single cell sequencing. We will simultaneously quantify epigenetic changes in chromatin organisation using ATACseq (Assay for Transposase-Accessible Chromatin using sequencing) and gene expression (RNAseq) in single T cells in response to extremally applied mechanical stress. Altogether, the data generated in the proposed research will provide us with a comprehensive understanding of how mechanical input delivered by dendritic cells regulate the initiation of the adaptive immune response. By revealing and deciphering a previously unexplored way of cell-cell communication in the immune system, these results will help building better immunotherapies approaches.

T淋巴细胞或T细胞在建立适应性免疫反应中起着核心作用，因为它们能够产生针对炎症类型和背景的反应，无论是感染还是发展中的肿瘤。这种能力与T细胞活化过程的特定性质有关，这是通过与抗原呈递细胞（免疫突触）的高度专业化界面实现的。抗原呈递细胞通过突触处的专用配体-受体系统激活和指导T细胞。在最近的一个项目中，我们发现树突状细胞，这是专业的抗原呈递细胞，另外通过免疫突触传递机械信号给T细胞。该项目的主要目标是了解机械输入（如树突状细胞产生的输入）如何影响T细胞激活的机制和结果。为此，我们将使用一种经过验证的细胞拉伸器，它可以产生类似于树突细胞在突触处产生的力的应力模式。在第一个目标中，我们将确定外力如何调节与T细胞活化相关的关键过程和信号通路，使用担架与活细胞显微镜中的荧光报告分子相结合。在第二个目标中，我们将改变规模，采用基于单细胞测序的多组学方法。我们将同时使用ATACseq（使用测序的转座酶可识别染色质测定法）和基因表达（RNAseq）定量单个T细胞中染色质组织的表观遗传变化，以响应极端施加的机械应力。总而言之，在拟议的研究中产生的数据将为我们提供一个全面的了解树突状细胞提供的机械输入如何调节适应性免疫反应的启动。通过揭示和破译免疫系统中以前未探索的细胞间通讯方式，这些结果将有助于建立更好的免疫治疗方法。