Regulation of Intestinal Dendritic Cell Development and Function

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The immune system in our intestine faces a formidable challenge, as it has to recognise, attack and destroy potentially harmful infectious agents, without compromising the health of the gut. However, it also has to ensure that it does not mount similar attacks against food or the innocuous bacteria that live in our intestine and which are essential for our health. However these harmless materials are not just ignored, as deliberate and active processes are triggered to make sure that the entire immune system cannot respond. This is called 'tolerance' and most people maintain a healthy balance between immune attack and tolerance. Inappropriate attacks on harmless foods or bacteria in the gut can cause chronic inflammation, such as coeliac disease or Crohn's disease, while ineffective immune responses mean intestinal infections remain major causes of morbidity and mortality worldwide. By understanding how the intestinal immune system decides how to react, we hope to find new ways of boosting responses when vaccinating against intestinal infections, and to develop new medicines for treating inflammatory bowel diseases. Cells called dendritic cells are crucial in all aspects of the immune response, as they decide whether active immunity or tolerance occurs. They do this by interpreting signals from the environment and instructing T lymphocytes how to react to the different foreign materials which enter the body. As there are several different kinds of dendritic cells, each with separate roles, it is thought that this could be exploited for deliberately manipulating immune responses in disease or for vaccines. The intestine contains many dendritic cells, where they are known to be important for controlling immune responses. However they have been difficult to study, partly because they are quite different from those found in other parts of the body and also because they have been confused with other cell types. We have recently developed more precise methods for studying the dendritic cells which are found in the lining of the intestine, the part of the gut where most foreign materials enter and where the first decisions need to be made about how to react. This has allowed us to identify new kinds of dendritic cell which have not been studied before and whose contribution to different types of immune response is not known. In this project, we will build on this initial work to understand more about the dendritic cells found in the intestine, using a mixture of sophisticated techniques to investigate how the various groups are related to each other and to study how they each behave when tolerance or active immunity is required. We have long experience in the field and will collaborate with international leaders in Sweden, France, Belgium and the USA, giving us access to an unrivalled mixture of methods. As a result, we hope to gain unique insights into a poorly characterised population of cells of critical importance for understanding the intestine and its immune system.