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

确定调节性 T 细胞通过整合素 alphavbeta8 和 TGF-beta 控制免疫的关键途径。

• 批准号: MR/M00242X/1
• 负责人: Mark Travis
• 金额: $ 61.62万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM00242X%2F1
• 关键词: Identifying; crucial; pathway; regulatory; cells

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.

我们的免疫系统必须对进入体内的病原体做出反应，以防止有害的感染。对抗感染的关键免疫细胞类型是T细胞。然而，除了它们的保护作用，T细胞有时会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，以及导致疾病的原因是什么。最近的研究已经确定了防止体内有害T细胞反应的关键细胞类型。因此，所谓的调节性T细胞（表达一种称为Foxp 3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，在具有导致缺乏调节性T细胞的突变的动物和人类中，都会发生严重的炎症性疾病。基于在动物模型中的有希望的结果，人们对调节性T细胞作为人类炎症性疾病的疗法（通过向患者注射调节性T细胞以抑制有害的T细胞应答）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非常重要，因此我们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。我们最近的新工作已经确定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。以前的研究表明，一种名为TGF-β的蛋白质在调节性T细胞的生物学中起着重要作用。许多细胞可以产生TGF-β，但它总是作为一种非活性复合物产生，需要被激活才能发挥作用。我们现在已经发现，调节性T细胞能够激活TGF-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 v β 8的特异性蛋白质。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 v β 8的调节性T细胞不再能抑制T细胞诱导的炎症。因此，这种新的整合素α v β 8-TGF-β通路的调节性T细胞似乎至关重要的能力，以控制有害的T细胞responses.However，仍然有许多重要的问题，我们的目标是解决在这个建议，使用小鼠模型和人类组织样本的组合，从患者的炎症性疾病。因此，有几种不同类型的表达Foxp 3的调节性T细胞，我们将研究这些细胞的特定亚群是否能够通过整合素α v β 8更好地激活TGF-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细胞上的整合素如何激活TGF-β，促进其抑制有害T细胞反应的能力。我们还将研究除了炎症性肠病之外，该途径在其他炎症性疾病中是否重要。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，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细胞阻止T细胞反应导致炎症性疾病的关键方式。这些信息将在设计潜在的新疗法方面非常有用，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。

项目成果

Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

• DOI: 10.4049/jimmunol.1602033
• 发表时间: 2017-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Brignall R;Cauchy P;Bevington SL;Gorman B;Pisco AO;Bagnall J;Boddington C;Rowe W;England H;Rich K;Schmidt L;Dyer NP;Travis MA;Ott S;Jackson DA;Cockerill PN;Paszek P
• 通讯作者: Paszek P

Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis.

• DOI: 10.1126/scitranslmed.aao4755
• 发表时间: 2018-10-24
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Scott NA;Andrusaite A;Andersen P;Lawson M;Alcon-Giner C;Leclaire C;Caim S;Le Gall G;Shaw T;Connolly JPR;Roe AJ;Wessel H;Bravo-Blas A;Thomson CA;Kästele V;Wang P;Peterson DA;Bancroft A;Li X;Grencis R;Mowat AM;Hall LJ;Travis MA;Milling SWF;Mann ER
• 通讯作者: Mann ER

The Immunology of Breast Development.

乳房发育的免疫学。

• DOI: 10.1016/j.devcel.2015.08.015
• 发表时间: 2015
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Travis MA