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

T细胞保护我们免受感染和癌症的侵害，但在感染期间也会引发不必要的炎症和组织损伤。调节性T细胞（Treg）是一种特殊的免疫细胞类型，具有抑制功能。虽然大多数Treg细胞是在生命早期产生的，但在整个生命过程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，维持Treg群体对健康老龄化至关重要，而这些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反应维持缺陷也会损害Treg靶向生物技术，包括Treg细胞疗法、耐受性原疫苗和过敏原免疫疗法。虽然我们现在对Treg细胞的发育机制了解很多，但我们对Treg细胞的反应是如何维持的缺乏基本的了解。这项提议的目的是确定Treg反应是如何在正常条件下维持的，随着年龄和炎症。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，是长时间Treg反应所必需的。重点分析肺内Treg反应，本研究将利用小鼠模型确定静止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。测定正常、年龄、炎症条件下肺Treg反应中静止Treg细胞的分子特性、细胞关系和组织分布2。利用遗传命运定位和条件缺失实验确定小鼠肺稳态和炎症期间静止和激活Treg细胞的细胞命运和功能利用尖端的分子，DNA和RNA测序方法确定Treg细胞内休眠的分子机制。Treg生物学领域的先前研究重点一直放在组织中占主导地位的高度活化的Treg细胞上。通过重新定义我们对Treg反应的看法，我们将把研究的重点从活化的Treg细胞转移到它们的长寿命祖细胞上，从而为生物技术/药物开发带来新的认识和机会。这种基础的生物科学方法对于未来更有效地应用Treg细胞治疗自身免疫和过敏性疾病以及与年龄相关的炎症铺平道路是必要的。

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.