Elucidating inhibitory signalling in T cell activation using optogenetics

T细胞是我们免疫系统的重要组成部分，它可以消除感染，使我们保持健康，尽管我们经常接触病原体。T细胞包含一个复杂的信号网络，可以识别我们身体的细胞是否受到感染，但有时这种决策过程无效，并导致疾病。目前的许多药物都是为了操纵这些信号通路，以提高对感染或癌症的免疫反应。虽然在识别这些网络的部分方面已经取得了很大的进展，但我们也必须了解它们之间的动态联系，以了解这些疗法是如何起作用的，并有望改进它们。然而，对于大多数信令网络来说，这种知识仍然非常有限。为了解决这个问题，我们开发了新的分子工具来研究T细胞信号网络的动力学，通过设计对化学或光做出反应的输入，使我们能够在空间和时间上精确地控制信号传递。在拟议的工作中，我们将探索T细胞表达的抑制性受体如何影响下游的输出反应。有人提出，这些抑制性受体只控制信号网络的一部分，但这一结果很难得到证实。这一结果具有重要的后果，因为目前用于癌症患者治疗的许多“检查点”抑制剂针对的是抑制受体，如PD-1，因此需要了解它们在基础水平上是如何发挥作用的，以改善它们的临床功能。为了解决这一局限性，我们将开发和实施新的工具来在分子水平上研究这一假说。我们将创造抑制性受体，当它们在天然细胞环境中被配体激活时，其活性可以被光控制。这项拟议研究的第一个主要目标是绘制T细胞内信号网络如何解码PD-1受体结合的信息，以期确定信号网络中可能被新药或疗法控制的部分。其次，我们将扩展这一方法，以了解T细胞表达的一系列抑制性受体的作用机制，寻找它们功能之间的共同特征。最终的目标将利用光的力量作为细胞输入，以‘脉冲’T细胞激活，这是我们最近发现减少抑制性信号。我们将调查这些时变信号是如何被网络‘读取’的，以再次找到可能成为癌症患者改进治疗的新靶点的部分。

T cells are an essential part of our immune system that eliminate infections to keep us healthy despite constant exposure to pathogens. T cells contain an intricate signalling network that can identify whether the cells of our body have become infected, but sometimes this decision-making process is ineffective and leads to disease. Many current drugs are designed to manipulate these signalling pathways to improve the immune response to infection or cancer. Whilst great progress has been made in identifying the parts of these networks, we must also understand the dynamic connections between them to know how these therapies work and hopefully improve them. However, for most signalling networks this knowledge remains very limited. To address this, we develop new molecular tools to investigate the dynamics of the T cell signalling network by engineering inputs that respond to chemicals or light, giving us precise control over signalling in space and time.In the proposed work, we will explore how inhibitory receptors expressed by T cells affect the downstream output response. It has been suggested that these inhibitory receptors only control one part of the signalling network, but this result has been hard to verify. The result has important consequences, as many of the 'checkpoint' inhibitors currently used for treatments for cancer patients target inhibitory receptors, such as PD-1, so knowing how they work at the fundamental level is required to improve their clinical function. To address this limitation, we will develop and implement new tools to investigate this hypothesis at the molecular level. We will create inhibitory receptors whose activity can be controlled by light when engaged by their ligands within their native cellular environment. The first main objective of the proposed research is to map how the information from PD-1 receptor binding is decoded by the T cell intracellular signalling network, with the expectation of identifying parts of the signalling network that could be controlled by new drugs or therapies. Secondly, we will expand this approach to understand the mechanism of action for a diverse range of inhibitory receptors expressed by T cells, to look for common features between their function. The final objective will leverage the power of light as a cell input to 'pulse' T cell activation, which we have recently found to decrease inhibitory signalling. We will investigate how these time-varying signals are 'read' by the network, to again find parts that could be new targets for improved therapies for cancer patients.