Understanding lipid antigen presentation in intestinal homeostasis and inflammation

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Humans carry around 10 times more microorganisms in the intestine as total cells constituting our body. These microorganisms (predominantly bacteria) perform many important metabolic functions for example helping in the digestion of the food to allow the absorption of nutrients. However, to prevent uncontrolled overgrowth and dissemination of intestinal bacteria the human body had developed a great variety of strategies that allow bacterial containment within the intestine. As such, the human gastrointestinal tract houses the big bulk of the immune system, and many different cell types cooperate to maintain a healthy relationship with our gut flora. Importantly, alteration of this equilibrium can lead to the development of intestinal disorders like is the case of Inflammatory Bowel Disease (IBD) that affects 1 in 250 people in the UK. IBD comprises a mixture of life-long disorders that may be ameliorated with immunosuppressive drugs but not cured, with around 40% of patients being considered for surgery normally involving removal of the affected bowel. Added to this, IBD patients show up to 18% increased risk of colorectal cancer over 30 years post disease onset. Therefore understanding the factors that modulate the cross-talk between the intestinal flora and the immune cells is critical to identify new therapeutic targets for the treatment of intestinal diseases. This proposal centers on the understanding of the role of a population of immune cells, so called NKT cells, within the intestine, both in healthy conditions and during the development of IBD. NKT cells are known to be present in the gastrointestinal tract and they have been proposed to function in the containment of intestinal bacteria. In addition to this, NKT cells accumulate in the intestine of IBD patients where they may play a role in the initiation of the disease. However the mechanisms that regulate the activation of these cells and their role in the development of IBD remain unclear. We aim to deliver fundamental new insights into the mechanisms regulating NKT cell function within the intestine with the ultimate goal of manipulating this knowledge in our advantage to design new treatments for intestinal disorders.