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

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 (1). 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 (2,3). 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 (1,4), 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 (5). During infection, IFNg shared between T cells limits cytotoxic CD8 T cell differentiation and enhances memory formation (5). 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, you 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.

KEYWORDS

CD8 T cells, microscopy, 2-photon, differentiation, microenvironment.

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques, and imaging. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Students will also attend external scientific conferences where they will be expected to present the research findings.

KEY THEMES

Immunity

KEY PUBLICATIONS

1. Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells. Gérard et al (2013), Nat Immunol, 14, 356 – 363.
2. Modes of Communication between T Cells and Relevance for Immune Responses. Uhl et al (2020), IJMS, 21(8), 2674.
3. Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics, Zenke. et al (2020), Immunity 52(2):313-327.e7.
4. Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses. Gérard A. et al, (2013), Immunol Rev, 251, 80 - 96.
5. Paracrine Costimulation of IFN gamma Signaling by Integrins modulates CD8 T cell differentiation. Mahale, Krummel et al, (2018) PNAS, 115(45):11585-11590.