Systematically defining the T cell signalling network of the phosphatase CD45

最近的大流行将T细胞在抗击病毒感染方面的重要性带到了公共领域。特别是CD8+ T细胞通过杀死病毒感染的细胞来保护我们免受感染，如SARS-CoV-2。它们在成功应对疫苗接种方面也很重要，疫苗接种对预防传染病至关重要。疫苗接种效力随着年龄的增长而下降，老年人免受感染和相关死亡率的保护程度通常较低。这是由于T细胞数量减少以及对抗原的反应减弱。抗原被跨越T细胞细胞膜的蛋白质识别，被称为T细胞受体复合物。虽然T细胞必须对外来抗原迅速作出反应，但这必须与对自身产生的抗原的异常识别相平衡，否则会导致自身免疫反应和健康挑战，如关节炎。确定T细胞受体如何感知不同的信号强度并将其转化为T细胞行为的变化，将有助于更好地了解CD8+ T细胞在整个生命过程中抵抗感染以维持健康的功能。CD45是T细胞表面膜上最丰富的蛋白质之一。它有一个呈现在细胞外部的糖结构域，与细胞内部具有酶功能的结构域相连，被称为磷酸酶。这种酶结构域从底物蛋白中去除磷酸基团以控制其功能，重要的是，它是T细胞受体对抗原的正确反应所必需的。我们已经确定了新的CD45相互作用蛋白，这个研究项目将确定它们是如何被CD45调节的。这将使我们能够解剖CD45如何直接控制T细胞对抗原的激活。为此，我们建立了一个新的研究工具，使我们能够测量CD45与来自小鼠的活的未经操作的T细胞中的其他蛋白质的接近度。这项研究将更好地理解免疫细胞是如何被激活的，以及信号是如何传播以引发正确的反应的。这对于理解对感染的反应非常重要，但也可能为创造靶向CD45或其相互作用物的药物来控制T细胞激活的扩展开辟道路，当T细胞激活异常高或低时，这可能是有用的。

The recent pandemic has brought the importance of T cells in fighting viral infections to the the public sphere. CD8+ T cells in particular protect us from infections, such as SARS-CoV-2, by killing virally infected cells. They are also important in mounting successful responses to vaccinations, which are critical for the prevention of infectious diseases. Vaccination efficacy declines with age, with older people generally less protected from infections and related mortality. This is due to decreased T cell numbers as well as weaker responses to antigens. Antigens are recognised by proteins that span the cell membrane of T cells, known as the T cell receptor complex. While T cells must respond rapidly to foreign antigens, this must be balanced against aberrant recognition of self-generated antigens, which otherwise can lead to autoimmune responses and health challenges such as arthritis. Determining how different signal strengths are sensed by the T cell receptor and translated into changes in T cell behaviour will give a greater understanding of CD8+ T cell function in fighting infection to maintain health across the lifecourse. CD45 is amongst the most abundant proteins spanning the cell surface membrane of T cells. It has a sugary domain presented to the outside of the cell linked to a domain with enzymatic function on the inside of cells, known as a phosphatase. This enzyme domain removes phosphate groups from substrate proteins to control their functions, and, importantly, is required for correct responses of T cell receptors to antigens. We have identified new CD45-interacting proteins and this research project will define how they are regulated by CD45. This will enable us to dissect how CD45 directly controls T cell activation in response to antigen. To this end, we have built a new research tool that enables us to measure CD45 proximity to other proteins in live unmanipulated T cells from mice. This research will deliver a better understanding of how immune cells are activated and how signalling is propagated to elicit correct responses. This will be important for understanding responses to infections, but could also open up avenues to create drugs targeting CD45 or its interactors to control the extension of T cell activation, which could be useful when T cell activation is aberrantly high or low.