Manipulating autophagy and related pathways to optimise intestinal Treg cell function and ameliorate intestinal inflammation.

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The human gut hosts a huge number of bacteria which live in a beneficial co-existence with us - we provide space and nutrients for them, while they help prevent infection by harmful bacteria. This co-existence is possible because our immune system learns to tolerate these beneficial bacteria, while remaining alert towards harmful bacteria that reach our intestine. However, in some individuals this tolerance stops working and the immune system attacks the beneficial bacteria. This can lead to the development of inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the gut. The causes of IBD are not fully understood and there is currently no cure, but treatment involves long-term administration of drugs which suppress the immune system. The symptoms of IBD and the side-effects of the drugs used in treatment have detrimental effects on patients' quality of life and, in many cases, surgery is required to remove affected regions of the gut. In addition, the course of disease and response to current therapies varies widely in individual IBD patients. To develop new and improved therapies a better understanding of the immune system in the intestine during IBD is crucial. It is known that IBD has a genetic component and is more likely to develop in humans who have changes to specific genes. Several of these genes are important for a process called autophagy - a key pathway used to degrade and recycle damaged components inside our cells. Studies from our group and others have shown that an important subset of white blood cells called T cells, as well as the epithelial cells that line the human gut, require autophagy for their optimal function. A subtype the T cells, called regulatory T cells, are essential for preserving tolerance in the human gut, where they are present in high frequencies. However, we have found that they are greatly reduced in the gut and are impaired in their function if the process of autophagy is absent. In this project, we aim to better understand how autophagy controls the survival and function of regulatory T cells in the gut. We will use a type of analysis called bioinformatics to compare thousands of normal and autophagy-deficient regulatory T cells. This will allow us to identify key molecules and pathways in regulatory T cells that are controlled by autophagy. We will grow regulatory T cells in the laboratory to check how manipulation of these molecules and pathways (e.g. using drugs) affects the development and survival of regulatory T cells. We will use our results to make alterations to the autophagy-deficient regulatory T cells to circumvent their defects and restore their function. In the final part of the project, we will use mouse models of IBD to investigate if inducing autophagy can prevent or cure intestinal inflammation. As autophagy is a process that occurs in all cells, we will use genetically modified mice in which specific types of cells are rendered autophagy-deficient to help us define how autophagy can affact different stages of disease.Overall, our project will help us to devise new ways to target the process of autophagy to alleviate harmful inflammation in the gut. This may eventually lead to new treatments for IBD patients, especially those who have alterations in genes that are linked to autophagy.