Intraepithelial T lymphocytes (IEL) are at the forefront of mucosal immunity - the first immune cells that pathogens encounter in the gut. IEL are central to the protection of the gut against infection and dietary stress, but dysregulated IEL responses are also associated with autoimmune inflammatory bowel diseases such as Coeliac and Crohn’s disease. Importantly, these specialised T cells reside between nutrient-absorptive intestinal epithelial cells, close to the anaerobic microbes in the intestinal lumen. This specialized environment dictates the fuels and oxygen available to IEL and metabolites that influence their function. The aim of this project is to investigate how metabolic adaptation of IEL to the intestinal environment, allows IEL to gain the necessary energy to drive appropriate responses to intestinal metabolic perturbations, including diet and microbial challenges. We will explore how cellular bioenergetics, macromolecule biosynthesis, redox balance, and metabolite waste management are regulated in IEL. In this project, the student will learn to use state-of-the-art techniques to study metabolism, including metabolomics with isotope labelling of metabolites followed by mass spectrometry, high-resolution imaging, signalling studies to investigate the pathways regulating IEL metabolic adaptations, and in vivo models to address how perturbations in these pathways regulate intestinal homeostasis. These studies will provide us with fundamental insights into how these unique immune cells adapt to their environment to maintain intestinal homeostasis, findings that can be leveraged therapeutically to tune IEL activity in infectious, autoimmune and/or metabolic diseases.
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