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Immune interactions at the intestinal epithelium
Inflammatory bowel diseases (IBD) and colon cancer are both diseases involving the intestinal epithelium, the single layer of epithelial cells that serves dual functions of nutrient absorption and protection from the external environment. Within the epithelial layer exists a group of unconventional innate-like T cells known as intraepithelial lymphocytes (IEL), that assimilate information from these luminal nutrients and microbes, and communicate with the epithelium and other immune cells to help maintain a balance between tolerance and resistance. Our main research interest is to understand how intestinal IEL coordinate immune responses to chemical, dietary and microbial inputs at the intestinal epithelium. In particular, we are driven by the hypothesis that IEL mainly communicate with epithelial cells to monitor the status of the gut and initiate appropriate responses. Thus, we are focussed on identifying the molecules that IEL and intestinal epithelial cells use to communicate with each other, and on dissecting the signalling pathways that are triggered in IEL by the different inputs.
Most IEL are T cells, and constantly patrol the length of the intestinal epithelium. Their patrolling behaviour, and the expression of large amounts of cytotoxic proteases has led to the suggestion that these cells monitor the epithelium for disruption or stress, and then kill the offending cell. However, it is not clear whether the response is tailored to suit the type of insult faced by the epithelium. IEL could kill infected or dysregulated cells, enhance repair of damaged epithelium, regulate the innate and adaptive immune responses, and develop memory, effectively maintaining intestinal homeostasis. Yet direct evidence of the involvement of IEL in these processes is lacking, and we do not understand the nature of the inputs that drive IEL function. Therefore, my lab seeks to address these questions:
- What are the contributions of IEL to maintaining gut homeostasis, and to protecting the gut from infection?
- How do IEL respond to intestinal infections and orchestrate the immune response?
- What are the signalling pathways that drive IEL function?
- How do dietary nutrients affect IEL function and how do IEL influence dietary responses?
- How are IEL metabolically adapted to the gut environment?
Our approach to dissecting the functional roles IEL play in intestinal homeostasis and disease, is to use a combination of proteomics, mouse models, intestinal infections, phospho-proteomic and multiplexed single-cell phosphoprotein analyses, and epithelial organoid:IEL co-cultures in vitro. Since setting up my research lab, we have generated key tools to study IEL biology and in-depth proteomic analyses that have allowed us to build hypotheses on the roles and regulation of IEL (Brenes, Vandereyken et al, 2021). Our discovery of the PIM kinases as important regulators of IEL function (James et al, 2021) has opened a new area of research in my lab. We have investigated the effects of the IEL cytokine IL-22 on epithelial cells, and found that transformed epithelial cells do not respond to IL-22 (Chen et al, 2019). We are determining the roles of the cytotoxic proteases Granzyme A and Granzyme B in the protective functions of IEL (Vandereyken et al, Biorxiv, 2021). We have also obtained exciting and unexpected insights into IEL biology by investigating how IL-15 and the T cell antigen receptor activate IEL function. The principles governing IEL activation and killing will also contribute greatly to our understanding of inflammatory bowel diseases, and potentially inform cancer immunology studies, where IEL play important roles.