The Role of Lung-Resident Memory Th2 cells in Asthma

项目摘要 定义记忆T辅助2型(Th2)细胞如何启动对空气变应原的召回反应具有潜在的 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。在……期间 疾病缓解，大约5%-10%的Th2效应细胞驱动过敏性哮喘导致长寿 准备好在过敏原再次暴露时做出反应的记忆细胞。因此，靶向记忆Th2细胞 激活是一种有吸引力的治疗策略。然而，目前还不清楚过敏原是如何吸入的。 启动内存Th2单元响应。最近，记忆T细胞生物学领域出现了一种新的范式 驻留在非淋巴组织中的组织驻留记忆T细胞(Trm)迅速启动回忆反应。 虽然组织驻留的Th2细胞(Th2-Trm)已经被描述，但这个群体在 促进过敏性炎症的作用尚不清楚。这项提案的目标是界定 Th2-Trm在肺中持续存在，对吸入的过敏原产生回忆反应。我们的中心假设是 Th2-Trm通过对同源抗原的快速和增强反应而点燃过敏性呼吸道炎症 将循环中的Th2细胞招募到抗原提呈部位的能力。从机制上讲，我们假设 Th2-Trm与表达Th2细胞趋化因子CCL17及以后的树突状细胞(DC)共定位 过敏原再激发迅速产生2型细胞因子，引发过敏性炎症并显著诱导 CCL17的DC表达。这种增强的CCL17表达从血液中招募循环中的Th2细胞到 抗原呈递部位被激活，放大过敏性炎症。我们建议使用 创新的实验系统，以确定Th2-Trm的功能，包括变态反应原治疗和 一种新的CCL17/CCL22报告小鼠--幼稚小鼠及其呼吸道粘膜的单细胞RNA序列分析 来自过敏性哮喘患者的T细胞。具体地说，我们建议(1)定义Th2-Trm在 调节反复发作的过敏性呼吸道炎症和(2)确定CCL17在调节Th2-Trm中的作用 本土化和功能化。拉希米博士将在免疫学中心执行K08提案中的工作 和炎症性疾病(CIID)在马萨诸塞州总医院(MGH)在博士的指导下。 安德鲁·勒斯特。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，是麻省理工学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、生物信息学等课程 和人类翻译研究，并组织了一个培训咨询委员会，以提供专业知识和 在这些领域提供援助。这个K08奖项的目标是为拉希米博士提供智力和 接受技术培训，成为一名独立的、由R01资助的具有免疫学专业知识的研究人员 过敏性哮喘和其他慢性嗜酸性肺病的致病机制。

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.