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，但在感染期间可以驱动不必要的炎症和组织损伤。调节性T（Treg）细胞是具有抑制功能的特化免疫细胞类型。虽然大多数Treg细胞在生命早期产生，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性和过敏性炎症。因此，Treg群体的维持对于健康老龄化至关重要，并且缺陷是炎性疾病的基础，包括年龄相关性炎症，也称为炎症。Treg应答的缺陷维持也损害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。虽然现在对Treg细胞如何发育有了很多了解，但我们对Treg反应如何维持缺乏基本的了解。该提案的目的是确定Treg反应如何在正常条件下以及随着年龄和炎症而维持。 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Treg反应所必需的。本研究将重点分析肺内Treg反应，使用小鼠模型确定静止Treg细胞的分子和细胞特性和功能，检查它们与正常条件下的其他Treg细胞以及与年龄和炎症的关系。 具体而言，我们的目标是：1。确定在正常条件、年龄和炎症下肺的Treg应答中静止Treg细胞的分子特性、细胞关系和组织分布2.在小鼠中使用遗传命运作图和条件性缺失实验确定肺稳态和炎症期间静止和活化Treg细胞的细胞命运和功能3.使用基于尖端分子、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Treg生物学领域中先前研究的焦点一直是在组织内占主导地位的高度活化的Treg细胞。通过重新定义我们如何看待Treg反应，我们将把研究重点从活化的Treg细胞转移到它们的长寿祖细胞，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是必要的，为Treg细胞未来更有效地治疗自身免疫性和过敏性疾病以及年龄相关炎症的个体铺平了道路。

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.