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

我们的免疫系统必须对进入人体的病原体做出反应，以防止有害的感染。对抗感染的一种关键免疫细胞类型是T细胞。然而，除了它们的保护作用外，T细胞有时还可以攻击我们自己的身体，导致毁灭性的炎症性疾病，如炎症性肠病和多发性硬化症。因此，医学研究的一个重要领域旨在确定T细胞通常是如何防止引起炎症性疾病的，以及哪些问题会导致疾病。最近的研究发现了一种关键的细胞类型，可以防止体内有害的T细胞反应。因此，所谓的调节性T细胞(表达一种名为Foxp3的特定蛋白质分子)是一种特殊类型的T细胞，可以抑制有害的免疫反应。事实上，在动物和人类中，如果突变导致缺乏调节性T细胞，就会发生严重的炎症性疾病。基于动物模型中可喜的结果，人们对调节性T细胞作为人类炎症性疾病的潜在疗法(通过给患者注射调节性T细胞以抑制有害的T细胞反应)的潜在用途非常感兴趣。因此，了解调节性T细胞抑制有害免疫反应的方式是极其重要的，这样我们就可以利用这些信息来设计更好的基于调节性T细胞的炎症性疾病治疗方法。我们最近的新工作发现了一种新的重要途径，调节性T细胞通过这种途径抑制有害的T细胞反应。先前的工作表明，一种名为转化生长因子-β的蛋白质在调节性T细胞的生物学中发挥着重要作用。许多细胞可以产生转化生长因子-β，但它总是以非活性复合体的形式产生，需要激活才能发挥作用。我们现在已经发现，调节性T细胞能够激活转化生长因子-β，并且这种激活需要调节性T细胞表达一种称为整合素α-β8的特定蛋白。重要的是，使用炎症性肠病的动物模型，我们发现不表达整合素α-β8的调节性T细胞不再能抑制T细胞诱导的炎症。因此，调节性T细胞上的这种新的整合素α-β8-转化生长因子-β途径似乎对它们控制有害T细胞反应的能力至关重要。然而，在这项建议中，我们仍然有许多重要的问题需要解决，使用的是小鼠模型和来自炎症性疾病患者的人类组织样本。因此，有几种不同类型的调节性T细胞表达Foxp3，我们将寻找这些细胞中的特定亚群是否能够更好地通过整合素α-β8激活转化生长因子-β并抑制T细胞反应。此外，我们的目标是详细确定调节性T细胞上整合素激活的转化生长因子-β如何促进其抑制有害T细胞反应的能力。我们还将研究该通路是否在炎症性肠病之外的其他炎症性疾病中也很重要。最后，我们将使用从当地医院获得的患者样本中分离的细胞，来发现该途径在人类炎症性疾病中是否重要。因此，我们的工作将确定调节性T细胞防止T细胞反应导致炎症性疾病的关键方法。这些信息将对设计潜在的新疗法非常有用，旨在促进调节性T细胞抑制T细胞引起的有害炎症的能力。

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.