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，使我们在不断接触病原体的情况下保持健康。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被感染，但有时这个决策过程是无效的，导致疾病。目前的许多药物都是为了操纵这些信号通路来改善对感染或癌症的免疫反应。虽然在识别这些网络的各个部分方面已经取得了很大的进展，但我们还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，并有希望改善它们。然而，对于大多数信号网络来说，这方面的知识仍然非常有限。为了解决这个问题，我们开发了新的分子工具，通过对化学物质或光作出反应的工程输入来研究T细胞信号网络的动力学，从而使我们能够在空间和时间上精确控制信号。在提出的工作中，我们将探讨T细胞表达的抑制性受体如何影响下游输出反应。有人认为这些抑制受体只控制信号网络的一部分，但这一结果很难证实。这一结果具有重要意义，因为目前用于治疗癌症患者的许多“检查点”抑制剂靶向抑制受体，如PD-1，因此了解它们在基础水平上的工作原理是改善其临床功能所必需的。为了解决这一限制，我们将开发和实施新的工具，在分子水平上研究这一假设。我们将创造抑制受体，其活性可以由光控制，当它们的配体在其原生细胞环境中参与。提出的研究的第一个主要目标是绘制来自PD-1受体结合的信息如何被T细胞内信号网络解码，并期望识别可由新药或疗法控制的信号网络部分。其次，我们将扩展这种方法，以了解T细胞表达的多种抑制受体的作用机制，寻找它们功能之间的共同特征。最终目标将利用光作为细胞输入的能量来“脉冲”T细胞激活，我们最近发现它可以减少抑制性信号。我们将研究这些时变信号是如何被神经网络“读取”的，以再次找到可能成为改进癌症患者治疗新靶点的部分。

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.