MechanoROS-T: Exploring mechanoregulated hydrogen peroxide as a mechanism of T cell activation

MechanoROS-T：探索机械调节的过氧化氢作为 T 细胞激活的机制

• 批准号: EP/Z000114/1
• 负责人: Hayley Sharpe
• 金额: $ 220.94万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ000114%2F1
• 关键词: MechanoROS; Exploring; mechanoregulated; hydrogen; peroxide

T cells mediate immune responses against infection. They scan our tissues for foreign antigens that that are recognised by cell surfaceT cell receptors (TCRs). Antigen-TCR binding initiates signalling cascades to promote effector functions including cytokine release,proliferation and cytotoxicity. Insights into T cell signalling are key to optimising T cell-based therapies in cancer. Despite itsimportance, how antigen-TCR binding initiates signalling inside the cell is an important unresolved question.Recent structural studies suggest the TCR is rigid and signals without conformational changes, a common cell surface receptoractivation paradigm. Prevailing models in the field draw on the role of receptor tyrosine phosphatases, such as CD45, and TCRmechanosensing properties. Neither fully explains TCR triggering. The immune system exploits reactive oxygen species such ashydrogen peroxide for pathogen killing and as a signalling second messenger - a chemical that modifies proteins and changes theirfunction. Our preliminary data reveals an important new function for hydrogen peroxide in regulating phosphatase-proteininteractions. Here, I propose two new concepts in TCR signalling: 1. Antigen-TCR binding mediates the mechanoregulation of secondmessenger hydrogen peroxide; and 2. Control of target protein phosphorylation and localisation by phosphatases is redox-regulated.My team will use three new mouse models developed in my lab to investigate these concepts. The first enables high-resolutionimaging of hydrogen peroxide spatiotemporal dynamics in primary T cells. The second will facilitate identification of CD45 proximalproteins in primary cells. Finally, a CD45 mutant with impaired redox sensing will allow us to assess its impact on T cell effectorfunctions in vivo. This work will not only deliver fundamental insights into T cell signalling, but also has transformative potential forbroader areas of cell-cell communication, and optimisation of T cell based immunotherapies.

T细胞介导针对感染的免疫应答。他们扫描我们的组织，寻找被细胞表面T细胞受体（TCR）识别的外来抗原。抗原-TCR结合启动信号传导级联以促进效应子功能，包括细胞因子释放、增殖和细胞毒性。深入了解T细胞信号传导是优化基于T细胞的癌症治疗的关键。尽管抗原-TCR结合很重要，但如何在细胞内启动信号传导是一个重要的未解决的问题。最近的结构研究表明，TCR是刚性的，没有构象变化就发出信号，这是一种常见的细胞表面受体激活模式。该领域的流行模型利用了受体酪氨酸磷酸酶（如CD 45）和TCR机械传感特性的作用。也不能完全解释TCR的触发。免疫系统利用活性氧物质如过氧化氢来杀死病原体，并作为信号第二信使-一种修饰蛋白质并改变其功能的化学物质。我们的初步数据揭示了过氧化氢在调节磷酸酶-蛋白质相互作用中的重要新功能。在这里，我提出两个新的概念，在TCR信号：1。抗原-TCR结合介导第二信使过氧化氢的机械调节;和2.磷酸酶对靶蛋白磷酸化和定位的控制是由氧化还原调节的。我的团队将使用我实验室开发的三种新的小鼠模型来研究这些概念。第一种方法能够对原代T细胞中的过氧化氢时空动力学进行高分辨率成像。第二个将有助于鉴定原代细胞中的CD 45近端蛋白。最后，氧化还原敏感受损的CD 45突变体将使我们能够评估其对体内T细胞效应功能的影响。这项工作不仅将提供对T细胞信号传导的基本见解，而且还具有更广泛的细胞间通讯领域的变革潜力，以及基于T细胞的免疫疗法的优化。