Role of MAIT cells in a mouse model of spontaneous colitis

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Project Summary. Inflammatory bowel diseases (IBD) are chronic and cause significant morbidity. An estimated 3 million adults in the USA currently live with IBD and no cure is available. It is clear that the disease is complex with influences from host genetics, microbiota and the immune system. Therefore, further understanding of the interplay between these factors is crucial to developing novel immunotherapies. Previous mouse models of IBD are limited for studying human disease, entailing the artificial induction of IBD in susceptible mice. Newer models of spontaneous colitis are necessary to dissect the roles of novel immune players and their ability to modulate disease and serve as therapeutic targets. Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T lymphocytes, highly abundant in human blood and in mucosal tissues, including the gut. They are potently activated by bacterial-derived metabolites presented by the evolutionary conserved major histocompatibility complex class I-related molecule, MR1. To date, they have been implicated in a range of inflammatory diseases. However, their role in IBD and the possible correlations between their involvement and the course of the disease remains uncertain. Patients with IBD demonstrate significant infiltration of MAIT cells into inflamed gut tissue and display an inflammatory profile. We have identified a new inbred mouse strain with high numbers of MAIT cells in primary immune organs and peripheral tissues, including the colon, compared to other mouse strains analyzed to date. These mice spontaneously develops pathologic features of colitis that emulate the human disease. We propose to test the hypothesis that increased MAIT cell numbers in these mice affects their susceptibility to colitis. The objectives of this project are to establish the interplay of how MAIT cells, microbiota and genetics lead to the development of spontaneous colitis. In Aim1, we will assess the dynamics of MAIT cell accumulation, activation and gene expression profile of the gut leukocytes of this new mouse strain as a function of age. In Aim 2, we will examine the contributions that MAIT cells and/or the microbiota both have towards the development of colitis in this new mouse strain. These studies will open up new possibilities for understanding the potential role of MAIT cells in colitis so that it can be exploited for therapeutic usage to improve human health.