Molecular mechanisms enabling cDC2s to control Th2 cell priming

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The intestine is a continuous tube that starts from the mouth and ends at the anus. It is home to the largest number of immune cells in the body. The reason for this is that the intestine is constantly exposed both to billions of harmless and beneficial microorganisms, and also to microbes that can cause infections. The immune cells in the intestine therefore face a formidable challenge. They have to recognise, attack and destroy potentially harmful infectious agents without damaging the body, but they must not mount similar attacks against food, or harmless microorganisms. These harmless materials are not just ignored, active processes are triggered to make sure that immune cells cannot respond to them and cause unnecessary damage to the body. It is important to understand how these immune responses in the intestine are controlled, so that we can find better ways to both activate these responses (e.g. for vaccination, or to control infection), and to reduce their strength when they cause damage to the intestine (e.g. during inflammatory bowel disease). The two cell types that are most important for controlling immune responses in the intestine are "dendritic cells" and "T cells". These cells interact with each other, and the outcome of this interaction defines the type of immune responses that are generated. Dendritic cells are found in the wall of the intestine, where they are able to acquire samples of proteins from their local environment, from food and microbes. After acquiring these proteins, the dendritic cells leave the intestine and travel to lymph nodes, where the T cells are found. Depending on the source of the protein the dendritic cell has acquired, the dendritic cell will cause the T cell to respond in different ways. For instance, if the dendritic cell has taken up protein from food, the T cell will be de-activated, so that an immune response is not accidentally made against a harmless food protein. On the other hand, the dendritic cell has acquired proteins from a harmful microbe, the dendritic cell will be activated by signals it will have also received from the microbe. This activated dendritic cell will then cause the responding T cell to become activated. The activated T cell will then be able to make a response against the microbe, and kill it. Different types of T cell responses are required to kill different types of microbes, so T cells activated to help kill bacteria will produce different molecules to T cells activated to help kill viruses or large parasitic organisms.This response is difficult to study because very small numbers of dendritic cell : T cell interactions have very large effects on the type of response that then occurs. It has been very challenging to discover the details of how these small numbers of dendritic cells work. By studying immune responses to parasites, we have recently identified two molecules that appear to have important effects on dendritic cell functions. Our project has two objectives. The first is to investigate how these two molecules work, and therefore understand the details of how dendritic cells control this type of immune response. Our second objective is to use methods we have developed to identify new molecules that are important for controlling immune responses in the intestine. To achieve this second objective we will take advantage of new technology that is able to identify many of the molecules produced by very small numbers of cells within larger populations. Understanding the functions of dendritic cells in the way we propose should help us to manipulate the immune response in a wide range of important situations, perhaps by improving the efficiency of vaccines, or preventing the inappropriate and damaging immune responses that cause the symptoms of inflammatory bowel disease.