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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：
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
项目类别：
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

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.

项目总结