Differential control of T cell co-stimulation by LFA-1, CD2, and CD28

适应性免疫系统是我们对抗入侵病原体的个性化武器，T细胞在其中发挥核心作用。一旦识别抗原，通过其T细胞抗原受体(TCR)，呈现为抗原提呈细胞上的肽-MHC(PMHC)复合体，T细胞就可以被激活，导致启动适应性免疫反应，清除病原体。根据T细胞激活的双信号假说，pMHC与抗原的相互作用是激活所必需的，但不是充分的。事实上，共刺激受体一旦与抗原提呈细胞(APC)上的配体结合，就提供了一个必要的第二信号，使激活得以进行。然而，尽管大量的分子研究强调了它们的结构和信号的多样性，但单个共刺激受体在T细胞功能反应中的不同作用仍然不清楚。例如，共刺激受体LFA-1、CD2和CD28是结构不同的家族的一部分，尽管分子机制不同，但都能增加T细胞对抗原的敏感性，LFA-1和CD2被归类为黏附分子，而CD28不被归类为黏附分子。这就提出了一个问题，即这些共刺激受体是否在功能上是多余的，或者它们在其他T细胞反应上是否具有不同的表型。利用实验和计算相结合的方法，我们的目标是揭示每个受体在T细胞激活的功能表型上的单独作用，这对改进免疫治疗具有重要的意义。这个项目涵盖了BBSRC的优先领域：“生物科学的系统方法”。从实验中收集的数据与数学模型结合使用，以更好地了解单个辅助受体在T细胞激活中的作用。

The adaptive immune system is our personalised weapon against invading pathogens with T cells playing a central role within it. Upon recognising antigens, presented as peptide-MHC (pMHC) complexes on antigen-presenting cells, viatheir T cell antigen receptors (TCRs), T cells can be activated, leading to the initiation of an adaptive immune response that clears the pathogen. According to the 2-signal hypothesis of T cell activation, the pMHC-antigen interaction isnecessary but not sufficient for activation. Indeed, co-stimulatory receptors, once engaged with their ligand upon antigen presenting cells (APCs), provide an essential second signal that permits activation to proceed. However, despiteextensive molecular studies highlighting their structural and signalling diversity, the distinct roles of individual costimulatory receptors on the functional response of T cells remains unclear. For example, the co-stimulatory receptorsLFA-1, CD2, and CD28 are part of structurally distinct families yet are all known to increase the sensitivity of T cells to antigen, albeit through different molecular mechanisms, with LFA-1 and CD2, but not CD28, classified as adhesionmolecules. This raises the question of whether these co-stimulatory receptors are functionally redundant or whether they have different phenotypes on other T cell responses. Utilising a combined experimental and computationalapproach, we aim to uncover the individual role of each receptor on the functional phenotypes of T cell activation, which has important implications for improving immunotherapy.This project covers the BBSRC Priority Area of 'Systems Approaches to the Biosciences'. The data collected from experiments is used in conjunction with mathematical models to better understand the role of individual accessoryreceptors in T cell activation.