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

T细胞介导抵抗感染的免疫反应。它们扫描我们的组织，寻找能被细胞表面细胞受体（tcr）识别的外来抗原。抗原- tcr结合启动信号级联，促进包括细胞因子释放、增殖和细胞毒性在内的效应功能。深入了解T细胞信号是优化基于T细胞的癌症治疗的关键。尽管它很重要，但抗原- tcr结合如何启动细胞内的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，没有构象变化的信号，这是一种常见的细胞表面受体激活模式。该领域的主流模型利用了受体酪氨酸磷酸酶（如CD45）和tcr机械传感特性的作用。两者都不能完全解释TCR触发。免疫系统利用活性氧（如过氧化氢）来杀死病原体，并作为信号传导的第二信使——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-蛋白相互作用方面的重要新功能。在这里，我提出了TCR信号的两个新概念：1。抗原- tcr结合介导第二信使过氧化氢的机制调控和2。磷酸酶对靶蛋白磷酸化和定位的控制受氧化还原调节。我的团队将使用我实验室开发的三种新小鼠模型来研究这些概念。第一种技术能够对过氧化氢在原代T细胞中的时空动态进行高分辨率成像。第二种方法将有助于鉴定原代细胞中的CD45近端蛋白。最后，氧化还原感知受损的CD45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-细胞通信领域的变革潜力，以及基于T细胞的免疫疗法的优化。

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.