Identifying a crucial pathway by which regulatory T-cells control immunity via integrin alphavbeta8 and TGF-beta.

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Our immune system must respond to pathogens that enter the body to prevent harmful infection. A key immune cell type in fighting infections is the T-cell. However, in addition to their protective roles, T-cells can sometimes attack our own body, resulting in devastating inflammatory diseases such as inflammatory bowel disease and multiple sclerosis. Thus, an important area of medical research aims to determine how T-cells are normally prevented from causing inflammatory disease, and what goes wrong to cause disease.Recent studies have identified a crucial cell type in preventing harmful T-cell responses in the body. Thus, so-called regulatory T-cells (which express a particular protein molecule called Foxp3)are a specialised type of T-cell which dampen harmful immune responses. Indeed, in both animals and humans who have mutations resulting in a lack of regulatory T-cells, severe inflammatory disease occurs. Based on promising results in animal models, there is great interest in the potential use of regulatory T-cells as a therapy for human inflammatory disease (by injecting patients with regulatory T-cells to inhibit harmful T-cell responses). It is therefore extremely important to understand the ways in which regulatory T-cells suppress harmful immune responses, so we can use this information to design better regulatory T-cell-based therapies for inflammatory disease.Our new recent work has identified a novel, important pathway by which regulatory T-cells suppress harmful T-cell responses. Previous work has indicated that a protein called TGF-beta plays an important role in the biology of regulatory T-cells. Many cells can make TGF-beta, but it is always made as an inactive complex which needs to be activated to function. We have now found that regulatory T-cells are capable of activating TGF-beta, and that this activation requires the regulatory T-cell to express a specific protein called integrin alphav beta8. Importantly, using an animal model of inflammatory bowel disease, we find that regulatory T-cells that do not express integrin alphav beta8 can no longer suppress T-cell-induced inflammation. Thus, this novel integrin alphav beta8-TGF-beta pathway on regulatory T-cells appears crucial in their ability to control harmful T-cell responses.However, there are still many important questions which we aim to address in this proposal, using a combination of mouse models and human tissue samples from patients with inflammatory disease. Thus, there are several different types of regulatory T-cell expressing Foxp3, and we will look to identify if a particular subset of these cells are better able to activate TGF-beta via integrin alphav beta8 and suppress T-cell responses. Additionally, we aim to determine in detail how TGF-beta activation by the integrin on regulatory T-cells promotes their ability to inhibit harmful T-cell responses. We will also study whether the pathway is important in other inflammatory diseases in addition to inflammatory bowel disease. Finally, we will discover whether the pathway is important in human inflammatory disease, using cells isolated from patient samples acquired from local hospitals.Our work will therefore identify a crucial way in which regulatory T-cells prevent T-cell responses from causing inflammatory disease. Such information will be extremely useful in designing potential novel therapies, aimed at promoting the ability of regulatory T-cells to dampen harmful inflammation caused by T-cells.