Sampling the environment: Antigen presentation and T cell regulation by intestinal epithelial cells

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The human intestine hosts a huge number of friendly bacteria that live in a mutually beneficial arrangement with us - we provide a nutrient-rich habitat for them and they produce some vitamins and help prevent infection with harmful bacteria. The basis of this peaceful co-existence is that our immune system learns to tolerate these beneficial bacteria, while remaining poised to respond to any harmful bacteria that infect our intestine. However, in some individuals, this tolerance breaks down and the immune system attacks the beneficial bacteria, leading to the development of inflammatory bowel diseases (IBD), which are chronic, debilitating disorders of the intestine. The causes of IBD are not known and there is no current cure. Instead, treatment involves long-term administration of immune suppressive drugs, which have side effects that include an increased risk of infection and cancer. A better understanding on how the immune system malfunctions in the intestine during IBD is necessary in order to develop new and improved therapies. The cells that line the human gut are called intestinal epithelial cells, which form a key barrier that limits exposure of our immune system to the bacteria that live in our gut. However, how these epithelial cells interact with our immune system and contribute to the maintenance of tolerance in our intestine is not well understood. In this project we will investigate the response pattern of the intestinal epithelial cell in the healthy gut and during inflammation and specifically focus on the crosstalk between epithelial cells and the immune system and look at how this is altered during harmful inflammatory responses, like IBD. T helper cells, a type of white blood cells, represent one of the key cell types of the immune system. In IBD patients, the harmful inflammation is caused by T helper cells that respond to beneficial intestinal bacteria. However, T helper cells do not recognise the bacteria directly, but are activated by other types of white blood cells that take up and digest the bacteria and then present fragments of the bacterial proteins, termed antigens, on their surface. However, it has been found that intestinal epithelial cells are also capable of presenting antigens, but whether this leads to activation of T helper cells is unclear and it has been proposed that instead this may be an important way of inducing tolerance to beneficial bacteria in the intestine. The key aim of this project is to study how antigen presentation by intestinal epithelial cells influences T helper cells. To achieve this, we will use genetically modified mice in which the intestinal epithelial cells lack the ability to present antigens. We will analyze the T helper cell responses in the gut of those animals and examine if these change during different models of intestinal infection and inflammation. Any alterations will reveal how antigen presentation by intestinal epithelial cells impacts on the reactivity of the immune system towards intestinal bacteria. To identify key molecules involved in the crosstalk between intestinal epithelial cells and T helper cells, we will use a new technique that allows us to grow and culture the intestinal epithelial cells. The great advantage of this 'in vitro' system is that the factors and cells involved can be selectively manipulated and key pathways can be clearly identified. Furthermore, intestinal epithelial cells will be grown from healthy people or patients with IBD and tested for their ability to present antigen. A better understanding of how intestinal epithelial cells contribute towards the control of T helper cell responses in the gut may lead to the development of novel therapies for IBD.