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: 10310428
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310428
• 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; Gene Expression Profile; General Hospitals; Goals; Human; Immune; Immunity; Immunologics; Immunology; Inflammation; Inflammatory; Inhalation; Interdisciplinary Study; Investigation; Label; Ligands; Lung; Lung diseases; Massachusetts; Mediating; Memory; Mentors; Mentorship; Microscopy; Modeling; Mus; Operative Surgical Procedures; Parabiosis; Phase; Phenotype; Population; Positioning Attribute; Production; Property; Pyroglyphidae; Recurrence; Reporter; Reporting; Research; Research Personnel; Respiratory Mucosa; 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; asthma model; career development; chemokine; cytokine; in vivo; innovation; insight; mouse model; novel; pathogen; pulmonary function; 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.

项目概要 定义记忆 T 辅助细胞 2 型 (Th2) 细胞如何启动对空气过敏原的回忆反应具有潜力 改变我们对过敏性哮喘（最常见的哮喘亚型）的治疗方法。期间 疾病静止期，大约 5-10% 驱动过敏性哮喘的效应 Th2 细胞导致长寿 准备好在再次接触过敏原时做出反应的记忆细胞。因此，针对记忆 Th2 细胞 激活是一种有吸引力的治疗策略。然而，目前尚不清楚过敏原吸入如何 启动记忆 Th2 细胞反应。最近，记忆 T 细胞生物学的新范式出现在 持续存在于非淋巴组织中的组织驻留记忆 T 细胞 (Trm) 会迅速启动回忆反应。 虽然组织驻留记忆 Th2 细胞 (Th2-Trm) 已被描述，但该细胞群的功能 促进过敏性炎症尚不清楚。该提案的目的是定义机制，使 持续存在于肺部的 Th2-Trm 协调对吸入过敏原的回忆反应。我们的中心假设是 Th2-Trm 通过对同源抗原的快速和增强的反应引发过敏性气道炎症 将循环 Th2 细胞募集至抗原呈递位点的能力。从机制上讲，我们假设 Th2-Trm 与表达 Th2 细胞吸引趋化因子 CCL17 及之后的树突状细胞 (DC) 共定位 过敏原再次攻击迅速产生 2 型细胞因子，引发过敏性炎症并显着诱导 CCL17的DC表达。这种增强的 CCL17 表达会招募血液中的循环 Th2 细胞 抗原呈递位点被激活，从而放大过敏性炎症。我们建议使用 定义 Th2-Trm 功能的创新实验系统，包括经过敏原处理和 幼稚小鼠、新型 CCL17/CCL22 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。具体来说，我们建议（1）定义Th2-Trm的功能 调节复发性过敏性气道炎症以及 (2) 明确 CCL17 在调节 Th2-Trm 中的作用 定位和功能。 Rahimi 博士将在免疫学中心执行 K08 提案中的工作 麻省总医院 (MGH) 的炎症性疾病 (CIID) 博士的指导下。 安德鲁·卢斯特. CIID 是一个最先进的多学科研究中心，专注于研究机制 免疫介导的炎症性疾病，是麻省总医院免疫学研究的基础。拉希米博士 制定了职业发展计划，包括高级显微镜、生物信息学课程 和人类转化研究，并组织了一个培训咨询委员会，以提供专业知识和 这些领域的援助。 K08 奖项的目标是为 Rahimi 博士提供智力和 技术培训，成为一名独立的、R01 资助的、具有免疫学专业知识的研究者 驱动过敏性哮喘和其他慢性嗜酸粒细胞性肺部疾病的机制。

项目成果

Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.

• DOI: 10.1126/scitranslmed.aal3765
• 发表时间: 2017-12-13
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Lagares D;Santos A;Grasberger PE;Liu F;Probst CK;Rahimi RA;Sakai N;Kuehl T;Ryan J;Bhola P;Montero J;Kapoor M;Baron M;Varelas X;Tschumperlin DJ;Letai A;Tager AM
• 通讯作者: Tager AM