Tissue-specific T cell migration in the intestine

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The intestine contains more immune cells than any other organ in the body. The small intestine and the large intestine (the colon), though connected, perform different functions. The small intestine digests and absorbs food, while the large intestine absorbs water. Both parts of the intestine are constantly exposed to harmless or beneficial microorganisms, and also to other microbes that can cause infections that can be unpleasant at best, and life threatening at worst. The immune cells in our intestine therefore face a formidable challenge. They have to recognise, attack and destroy potentially harmful infectious agents without damaging the tissue, but not mount similar attacks against food or the innocuous microorganisms that live in our intestine. These harmless materials are not just ignored. Deliberate and active processes are triggered to make sure that immune cells cannot respond to them. Most people have a healthy intestine but ineffective immune responses mean intestinal infections remain major causes of illness and death worldwide. On the other hand, inappropriate attacks on harmless foods or microorganisms can cause inflammatory bowel disease (IBD). Crohn's disease and ulcerative colitis, are the commonest types of IBD. They are life-changing conditions and currently affect over a quarter of a million people in the UK. IBD can also substantially increase the likelihood of developing bowel cancer. Currently there is no cure, and existing medicines are often ineffective at treating symptoms. Our recent work has generated results that will enable us to identify the molecules that direct the immune cells to the intestine. Identifying these molecules will be a major step towards developing new therapies to treat IBD and new ways of boosting responses to immunisation against intestinal infections.Immune responses in the intestine start within specialised tissues called the mesenteric lymph nodes (MLN). This is a chain of lymph nodes linked end-to-end and connected to the intestine by specialised vessels. These vessels convey information from the intestine that is used by the MLN to instruct immune cells, which can then travel to the intestine to perform specific tasks. We have shown that each individual lymph node in the MLN chain performs distinct functions and appears to be responsible for a specific region of the intestine - The immune cells in a particular lymph node travel to a particular part of the intestine. This is important, because it means that immune cells can be directed to the place where they are most likely to be useful, and can therefore protect us efficiently. While in the MLN, immune cells make particular molecules that allow them travel to the correct part of the intestine. Two molecules have already been identified that contribute to directing immune cells specifically to the small intestine. Drugs have been developed for the treatment of IBD that interfere with the function of one or other of these two molecules. Other as yet unidentified molecules are also involved in directing immune cells to the small intestine, and very little is known about the molecules that direct immune cells to the large intestine. Our new discoveries about the specialisation of lymph nodes in the MLN chain provide us with an opportunity to compare immune cells in each of the different nodes, determine where they travel to in the intestine, and identify novel molecules required to get them there. We will also be able to determine how immune cells in different lymph nodes acquire the unique sets of molecules they need to get back to the intestine. We will investigate this in healthy animals, and in animals with inflammation in different parts of their intestines. We anticipate that this work will identify new ways to control how immune cells travel in the body, and therefore new strategies to prevent them causing harm in patients with IBD or novel ways of boosting immunisations against intestinal infections.