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

我们感兴趣的是了解适应性免疫系统的细胞，称为CD8T细胞，是如何在健康和疾病中在体内的空间和时间内招募和组织的。CD8T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强大的，从而在保持耐受性的同时有效地根除病原体。为了实现这种程度的全球协调，T细胞必须相互沟通和共同调节。我们最近发现CD8 T细胞通过使用整合素LFA-1及其配体ICAM-1形成T细胞-T细胞突触来相互作用。T细胞形成T-T突触，通过相互分享细胞因子来进行特定的通信。我们发现IFNG是在T-T突触介导T细胞通讯的一个关键细胞因子。在感染过程中，T细胞之间共享的IFNG限制了细胞毒性CD8 T细胞的分化，并增强了记忆的形成。然而，我们目前的数据显示，在癌症中，通过IFNG进行的T细胞通讯反而抑制了干细胞样T细胞的维持，增强了T细胞功能障碍。总体而言，这突出了这样一个事实，即T细胞通讯发生的微环境会影响结果。换句话说，T细胞通过感知它们所处的微环境来适应触发。我们的初步数据显示，即使在相同的组织内，对相同的触发因素做出反应，也会形成多个相互对比的微环境。在李斯特菌感染后，T细胞启动至少在两个微环境中发生。这个项目的目标是识别存在于不同微环境中的细胞和介体，并表征它们如何影响T细胞的启动和随后的分化。为了做到这一点，学生将使用传统的免疫学分析，多种显微镜技术，如共聚焦和双光子和NICE-SEQ。这些研究将确定CD8 T细胞如何整合它们从所在微环境接收的信号，最终使其对触发因素做出反应。了解CD8T细胞是如何分化的，以及促进这种分化的微环境可能具有治疗意义，例如对于疫苗设计。

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.