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

基本信息

批准号：
10065010
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
项目类别：
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/10065010
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 Mucous Membrane Mus Operative Surgical Procedures Parabiosis Phase Phenotype Population Positioning Attribute Production Property Pyroglyphidae Recurrence Reporter Reporting Research Research Personnel 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

项目摘要

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.

项目摘要定义记忆t辅助辅助型2（TH2）细胞如何启动对气溶剂的召回响应具有潜力为了改变我们对过敏性哮喘的理论方法，这是最常见的哮喘亚型。期间疾病静止，大约5-10％在过敏原重新暴露时被中毒的记忆细胞。因此，靶向内存th2单元激活是一种有吸引力的治疗策略。但是，尚不清楚如何吸入过敏原启动记忆Th2细胞响应。最近，记忆T细胞生物学中的新范式已经出现在非淋巴组织中，哪些组织居住的记忆T细胞（TRM）持续迅速引发回忆反应。虽然已经描述了组织居住的记忆Th2细胞（Th2-Trm），但该人群的功能在促进过敏性炎症尚不清楚。该提议的目的是定义机制 Th2-Trm坚持在肺部策划对吸入过敏原的召回反应。我们的中心假设是 Th2-Trm通过对同志抗原和能够募集循环Th2细胞到抗原表现部位的能力。从机械上讲，我们假设 Th2-TRM与表达Th2细胞趋化因子CCL17的树突状细胞（DC）共定位过敏原再挑战迅速产生启动过敏性注射并显着影响的2种细胞因子 CCL17的直流表达。这种增强的CCL17表达招募了从血液到血液循环的Th2细胞抗原表现的部位被激活，并放大过敏注射。我们建议使用定义Th2-TRM功能的创新实验系统，包括过敏原处理和幼稚的小鼠，一种新型的CCL17/CCL22记者小鼠以及气道粘膜的单细胞RNA-seq分析来自患有过敏性哮喘的人的T细胞。具体而言，我们建议（1）定义Th2-Trm的功能调节复发性过敏性气道注射，（2）定义CCL17在调节Th2-TRM中的作用本地化和功能。 Rahimi博士将在免疫学中心的这项K08提案中进行工作马萨诸塞州综合医院（MGH）的炎症性疾病（CIID）安德鲁·兰斯（Andrew Luster）。 CIID是一个最先进的多学科研究中心，重点是免疫介导的炎症性疾病是MGH免疫研究的基础。拉希米博士已经制定了一项职业发展计划，该计划包括高级显微镜，生物信息学的课程工作以及人类翻译研究以及组织一个培训咨询委员会，以提供专业知识和在这些领域的协助。该K08奖的目标是为Rahimi博士提供知识分子和技术培训成为一名具有免疫学专业知识的独立，R01资助的研究者驱动过敏性哮喘和其他慢性嗜酸性肺疾病的机制。