Illuminating T cells in their local microenvironments to understand how they sense and adapt to their trigger during infection

照亮局部微环境中的 T 细胞，了解它们在感染过程中如何感知和适应触发因素

• 批准号: 2886434
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2886434
• 关键词: Illuminating; cells; their; local; microenvironments

We are interested in understanding how cells of the adaptive immune system, called CD8 T cells, are recruited and organised in space and time in vivo in health and disease. CD8 T cells are plastic and heterogenous; however, their overall, collective response to pathogens is consistent and robust, resulting in efficient pathogen eradication while preserving tolerance. To achieve this level of global coordination, T cells have to communicate and co-regulate each other. We recently discovered that CD8 T cells interact with each other by forming T cell-T cell synapses, using the integrin LFA-1 and its ligand ICAM-1. T cells form T-T synapses to specifically communicate by sharing cytokines with each other. We identified IFNg as one key cytokine mediating T cell communication at T-T synapses. During infection, IFNg shared between T cells limits cytotoxic CD8 T cell differentiation and enhances memory formation. However, our current data shows that in cancer, T cell communication through IFNg rather inhibits stem-like T cell maintenance, enhancing T cell dysfunction. This overall highlights the fact that the microenvironments where T cell communication happens influences the outcome. In other words, T cells adapt their response to the trigger by sensing the microenvironment they reside in. Our preliminary data shows that even within the same tissue, and in response to the same trigger, multiple contrasting microenvironments form. Following Listeria infection, T cell priming occurs in at least two microenvironments. The goal of this project is to identify the cells and mediators present in different microenvironments and characterise how they influence T cell priming and subsequent differentiation. To do so, the student will use conventional immunological assays, multiple microscopy techniques such as confocal and 2-photon and niche-seq. These studies will identify how CD8 T cells integrate the signals they receive from the microenvironments they reside in to ultimately adapt their response to the trigger. Understanding how CD8 T cells differentiate and the microenvironments that foster this could have therapeutic implication, for example for vaccine design.

我们有兴趣了解适应性免疫系统的细胞，称为CD 8 T细胞，如何在健康和疾病的体内空间和时间中招募和组织。CD 8 T细胞是可塑性和异质性的;然而，它们对病原体的总体集体反应是一致和稳健的，导致有效的病原体根除，同时保持耐受性。为了达到这种水平的全球协调，T细胞必须相互沟通和共同调节。我们最近发现，CD 8 T细胞通过使用整合素LFA-1及其配体ICAM-1形成T细胞-T细胞突触而相互作用。T细胞形成T-T突触以通过彼此共享细胞因子来特异性地通信。我们将IFNg鉴定为在T-T突触处介导T细胞通讯的一种关键细胞因子。在感染期间，T细胞之间共享的IFNg限制细胞毒性CD 8 T细胞分化并增强记忆形成。然而，我们目前的数据显示，在癌症中，T细胞通过IFNg的通讯抑制了干细胞样T细胞的维持，增强了T细胞功能障碍。这总体上突出了T细胞通信发生的微环境影响结果的事实。换句话说，T细胞通过感知它们所处的微环境来适应它们对触发的反应。我们的初步数据表明，即使在同一组织内，并且响应于相同的触发，也会形成多种对比的微环境。李斯特菌感染后，T细胞引发发生在至少两种微环境中。该项目的目标是识别不同微环境中存在的细胞和介质，并研究它们如何影响T细胞引发和随后的分化。要做到这一点，学生将使用传统的免疫学测定，多种显微镜技术，如共聚焦和2-光子和niche-seq。这些研究将确定CD 8 T细胞如何整合它们从所处的微环境中接收的信号，以最终适应它们对触发的反应。了解CD 8 T细胞如何分化以及促进这种分化的微环境可能具有治疗意义，例如用于疫苗设计。