Amino acid availability acts as a critical environmental rheostat of mucosal ILC2 responses

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Our intestines are continually exposed to a wide range of stimuli from the environment in the form of bacteria - both beneficial and harmful - and metabolically active molecules released during the digestion of food. The immune system continually acts to keep the intestine healthy and functioning normally, and to prevent any damage caused by infections or chemicals entering the body during feeding. Recent advances have shown that the balance of bacterial and dietary-derived signals in the intestine dramatically alters the way the immune system responds, and changes in this balance can result in reduced immunity to infection, inflammation or even the progression of obesity or cancer. However, the precise nature of these environmental signals and the way immune cells respond to them remains unclear, blocking the development of new treatments aimed at modifying environmental signals in the gut, or targeting the immune cell sensors that detect them.In this project we will build upon new and exciting early work in our lab that suggest that a population of tissue-resident innate immune cells continually sense the intestinal environment for changes in a family of so-called "essential" amino acids. These amino acids are critical to keep us healthy but cannot be made by human cells and must be ingested from digestion of food in the diet. This particular population of gut-resident immune cells constantly surveys the intestine for potential danger, and responds quickly in response to danger or infections to launch protective immunity and to repair the tissue. The speed of this response is highly reliant on the ability to sense changes in the gut environment, as well as the cells ability to import basic building blocks of proteins - in the form of amino acids - that act to "fuel" immune function. We show these cells have a much higher ability to sense changes in intestinal amino acid levels compared to other immune cells, which allows them to generate an appropriate fast and powerful immune response. In this proposal we suggest that the ability of these immune cells to sense essential amino acids is critical for the intestinal immune system to sense infections or potential danger.We propose to further explore this hypothesis using exciting, new experimental tools and approaches which will allow us to determine exactly how these critical immune cells respond to changes in amino acids in the intestinal environment. In particular, we have identified two key genes that encode for amino acid "transporters" that detect and take up amino acids into immune cells. Using models in which these genes have been deleted within immune cells we have generated early findings which suggest the levels of amino acids both outside and inside an immune cell determine the degree to which that cell can perform it's tissue protective functions and respond to intestinal infection.Our central objectives are to utilize new technologies and experimental tools in the lab to better understand how immune cells sense their environment - particularly how they respond to changes in important nutrients and metabolites to ensure appropriate responses that subsequently keep our intestines healthy. These findings could have important consequences for a wide range of intestinal diseases by helping us to understand how environment risk factors such as diet and infections alter the function of the immune system and determine intestinal health.