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

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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.