Cellular and molecular organisation of long-lived immunoregulatory responses within the lung

肺内长效免疫调节反应的细胞和分子组织

• 批准号: BB/X006344/1
• 负责人: Rahul Roychoudhuri
• 金额: $ 77.55万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX006344%2F1
• 关键词: Cellular; molecular; organisation; long; lived

T cells defend us against infections and cancer but can drive unwanted inflammation and tissue damage during infection. Regulatory T (Treg) cells are a specialised immune cell type with suppressive function. While most Treg cells are generated early in life, maintenance of these cells throughout life prevents life-threatening autoimmune and allergic inflammation. Maintenance of Treg populations is therefore essential to healthy ageing, and defects underlie inflammatory disorders, including age-associated inflammation, also called inflammageing. Defective maintenance of Treg responses also impairs Treg-targeted biotechnologies, including Treg cell therapy, tolerogenic vaccines and allergen immunotherapy. While much is now known about how Treg cells develop, we lack a fundamental understanding of how Treg responses are maintained. The purpose of this proposal is to establish how Treg responses are maintained under normal conditions, and with age and inflammation. Some tissues in our body are maintained by stem cells. We have recently found that a critical property of stem cells, called quiescence, is required for long-lived Treg responses. Focussing our analyses on Treg responses wihtin the lung, this research will determine the molecular and cellular properties and functions of quiescent Treg cells using mouse models, examining their relationship with other Treg cells under normal conditions, and with age and inflammation. Specifically, we aim to: 1. Determine the the molecular properties, cellular relationships and tissue distribution of quiescent Treg cells within Treg responses of the lung under normal conditions, age and inflammation 2. Determine the cellular fate and functions of quiescent and activated Treg cells during lung homeostasis and inflammation using genetic fate-mapping and conditional deletion experiments in mice 3. Determine molecular mechanisms by which quiescence is programmed and maintained within Treg cells using cutting edge molecular, and DNA and RNA sequencing-based approaches The focus of prior research in the field of Treg biology has been on the highly activated Treg cells which predominate within tissues. By redefining how we think about Treg responses, we will shift focus of research from activated Treg cells to their long-lived progenitors, leading to new understanding and opportunities for biotechnology/drug development. This fundamental bioscience approach is necessary to pave the way for more effective future therapeutic applications of Treg cells for individuals with autoimmune and allergic disorders, and age-associated inflammation.

T 细胞可以保护我们免受感染和癌症的侵害，但在感染过程中可能会引发不必要的炎症和组织损伤。调节性 T (Treg) 细胞是一种具有抑制功能的特殊免疫细胞类型。虽然大多数 Treg 细胞是在生命早期产生的，但在一生中维持这些细胞可以防止危及生命的自身免疫和过敏性炎症。因此，Treg 群体的维持对于健康老龄化至关重要，而缺陷是炎症性疾病的基础，包括与年龄相关的炎症，也称为炎症。 Treg 反应的维持缺陷也会损害 Treg 靶向生物技术，包括 Treg 细胞疗法、致耐受性疫苗和过敏原免疫疗法。虽然现在人们对 Treg 细胞如何发育了解很多，但我们对 Treg 反应如何维持缺乏基本了解。该提案的目的是确定在正常条件下以及年龄和炎症情况下如何维持 Treg 反应。 我们体内的一些组织是由干细胞维持的。我们最近发现，干细胞的一个关键特性，称为静止，是长寿命 Treg 反应所必需的。这项研究的重点是对肺部 Treg 反应的分析，将使用小鼠模型确定静态 Treg 细胞的分子和细胞特性和功能，检查它们在正常条件下与其他 Treg 细胞的关系，以及与年龄和炎症的关系。 具体来说，我们的目标是： 1. 确定正常条件、年龄和炎症条件下肺部 Treg 反应中静止 Treg 细胞的分子特性、细胞关系和组织分布 2. 确定静止和激活 Treg 细胞的细胞命运和功能使用基因命运图谱和条件删除实验在小鼠中进行肺稳态和炎症期间的研究 3. 使用尖端分子以及基于 DNA 和 RNA 测序的方法确定 Treg 细胞内编程和维持静止的分子机制 先前研究的重点Treg 生物学领域的研究重点是组织内占主导地位的高度活化的 Treg 细胞。通过重新定义我们对 Treg 反应的看法，我们将把研究重点从活化的 Treg 细胞转移到其长寿的祖细胞上，从而为生物技术/药物开发带来新的理解和机会。这种基本的生物科学方法对于未来更有效地应用 Treg 细胞治疗患有自身免疫性疾病和过敏性疾病以及与年龄相关的炎症的个体铺平道路是必要的。