The Role of Lung-Resident Memory Th2 cells in Asthma

肺驻留记忆 Th2 细胞在哮喘中的作用

• 批准号: 9431929
• 负责人: Rod Amir Rahimi
• 金额: $ 17.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-08 至 2022-12-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9431929
• 关键词: Address; Adoptive Transfer; Advisory Committees; Allergens; Allergic inflammation; Anatomy; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Asthma; Automobile Driving; Award; Bioinformatics; Biology; Blood; CCL17 gene; CCL22 gene; Cardiovascular system; Cell physiology; Cells; Cellular biology; Chronic; Confocal Microscopy; Correlative Study; Data; Dendritic Cells; Development Plans; Disease; Environment; Eosinophilia; Exhibits; Extrinsic asthma; Flow Cytometry; Foundations; Funding; General Hospitals; Genetic Transcription; Goals; Human; Immune; Immunity; Immunologics; Immunology; Inflammation; Inflammatory; Inhalation; Interdisciplinary Study; Investigation; Label; Ligands; Lung; Lung diseases; Massachusetts; Mediating; Memory; Mentors; Mentorship; Microscopy; Modeling; Mucous Membrane; Mus; Operative Surgical Procedures; Parabiosis; Phase; Phenotype; Population; Positioning Attribute; Production; Property; Pyroglyphidae; Recurrence; Reporter; Reporting; Research; Research Personnel; Respiratory physiology; Role; Site; System; T memory cell; T-Lymphocyte; Techniques; Testing; Th2 Cells; Therapeutic; Tissues; Training; Transgenic Mice; Translational Research; Work; airborne allergen; allergic airway inflammation; career development; chemokine; cytokine; in vivo; innovation; insight; mouse model; novel; pathogen; recruit; response; single-cell RNA sequencing; transcriptome

Project Summary Defining how memory T helper type 2 (Th2) cells initiate a recall response to an aeroallergen has the potential to change our therapeutic approach to allergic asthma, the most common asthma subtype. During periods of disease quiescence, approximately 5-10% of effector Th2 cells driving allergic asthma give rise to long-lived memory cells that are poised to respond upon allergen re-exposure. Consequently, targeting memory Th2 cell activation is an attractive therapeutic strategy. However, it is not well understood how allergen inhalation initiates a memory Th2 cell response. Recently, a new paradigm in memory T cell biology has emerged in which tissue-resident memory T cells (Trm) persisting in non-lymphoid tissue rapidly initiate recall responses. While tissue-resident memory Th2 cells (Th2-Trm) have been described, the function of this population in promoting allergic inflammation is unclear. The objective of this proposal is to define the mechanisms whereby Th2-Trm persisting in the lung orchestrate a recall response to an inhaled allergen. Our central hypothesis is that Th2-Trm ignite allergic airway inflammation via a rapid and enhanced response to cognate antigen and the ability to recruit circulating Th2 cells to the sites of antigen presentation. Mechanistically, we hypothesize that Th2-Trm co-localize with dendritic cells (DCs) expressing the Th2 cell-attracting chemokine CCL17 and after allergen re-challenge rapidly produce type 2 cytokines that initiate allergic inflammation and markedly induce DC expression of CCL17. This enhanced CCL17 expression recruits circulating Th2 cells from the blood to sites of antigen presentation where they are activated, amplifying allergic inflammation. We propose to use innovative experimental systems to define the function of Th2-Trm, including parabiosis of allergen-treated and naïve mice, a novel CCL17/CCL22 reporter mouse as well as single cell RNA-seq analysis of airway mucosal T cells from humans with allergic asthma. Specifically, we propose (1) To define the function of Th2-Trm in regulating recurrent allergic airway inflammation and (2) To define the role of CCL17 in regulating Th2-Trm localization and function. Dr. Rahimi will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at Massachusetts General Hospital (MGH) under the mentorship of Dr. Andrew Luster. The CIID is a state-of-the-art multidisciplinary research center focused on mechanisms of immune-mediated inflammatory diseases and is the foundation for immunology research at MGH. Dr. Rahimi has developed a career development plan consisting of coursework in advanced microscopy, bioinformatics and human translational research as well as organized a Training Advisory Committee to provide expertise and assistance in these areas. The goal of this K08 award is to provide Dr. Rahimi with the intellectual and technical training to become an independent, R01-funded investigator with expertise in the immunologic mechanisms driving allergic asthma and other chronic eosinophilic lung diseases.

项目摘要 确定记忆性辅助性T细胞2型（Th 2）细胞如何启动对空气过敏原的回忆反应， 改变我们对过敏性哮喘的治疗方法，过敏性哮喘是最常见的哮喘亚型。时期 在疾病静止期，大约5-10%的效应Th 2细胞驱动过敏性哮喘引起长寿命的 记忆细胞准备对过敏原再次暴露做出反应。因此，靶向记忆Th 2细胞 活化是一种有吸引力的治疗策略。然而，目前还不清楚过敏原吸入是如何 启动记忆Th 2细胞应答。最近，在记忆T细胞生物学中出现了一种新的范式， 这种组织驻留记忆T细胞（Trm）持续存在于非淋巴组织中，迅速启动回忆反应。 虽然已经描述了组织驻留记忆性Th 2细胞（Th 2-Trm），但是该群体在免疫应答中的功能还不清楚。 促进过敏性炎症的原因尚不清楚。这项建议的目的是确定机制， 持续存在于肺中的Th 2-Trm协调对吸入性过敏原的回忆反应。我们的核心假设是 Th 2-Trm通过对同源抗原快速和增强的应答引发过敏性气道炎症， 将循环Th 2细胞募集到抗原呈递位点的能力。从机制上讲，我们假设 Th 2-Trm与表达Th 2细胞吸引趋化因子CCL 17的树突状细胞（DC）共定位， 过敏原再激发迅速产生2型细胞因子，其引发过敏性炎症并显著诱导 CCL 17的DC表达。这种增强的CCL 17表达从血液中募集循环Th 2细胞， 抗原呈递位点，在那里它们被激活，放大过敏性炎症。我们建议使用 创新的实验系统来定义Th 2-Trm的功能，包括过敏原处理的 未处理小鼠、新型CCL 17/CCL 22报告小鼠以及气道粘膜的单细胞RNA-seq分析 来自过敏性哮喘患者的T细胞。具体而言，我们建议（1）定义Th 2-Trm在 研究CCL 17在调节Th 2-Trm中的作用 定位和功能。Rahimi博士将在免疫学中心执行本K 08提案中的工作 和炎症性疾病（CIID）在马萨诸塞州总医院（MGH）的指导下，博士。 安德鲁·卢斯特CIID是一个最先进的多学科研究中心，专注于 免疫介导的炎症性疾病，是MGH免疫学研究的基础。Rahimi博士 制定了职业发展计划，包括高级显微镜、生物信息学等课程 和人类转化研究，并组织了一个培训咨询委员会，提供专业知识， 在这些领域的援助。这个K 08奖项的目标是为拉希米博士提供知识和 技术培训，成为一个独立的，R 01资助的研究者，具有免疫学专业知识， 导致过敏性哮喘和其他慢性嗜酸性肺病的机制。