Defining the development of tissue-resident memory Th2 cells in allergic asthma

定义过敏性哮喘中组织驻留记忆 Th2 细胞的发育

基本信息

批准号：
10501568
负责人：
Rod Amir Rahimi
金额：
$ 8.4万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10501568
关键词：
Address Allergens Allergic Allergic Disease Allergic inflammation Antigen-Presenting Cells Antigens Asthma Automobile Driving Award Biology CC chemokine receptor 4 CCL17 gene CCL22 gene CD4 Antigens CD4 Positive T Lymphocytes Caring Cell Communication Cell Death Cell physiology Chronic Data Dendritic Cells Dendritic cell activation Development Disease Extrinsic asthma Funding Gene Expression Genetic Transcription Goals Health Care Costs Helper-Inducer T-Lymphocyte Human Immunity Individual Inflammatory Interleukin-13 Interleukin-4 Interleukin-5 Investigation Journals Knockout Mice Ligands Lung Medicine Memory Modeling Morbidity - disease rate Mus Performance Peripheral Pilot Projects Population Positioning Attribute Proteins Pulmonary Inflammation Pyroglyphidae Reagent Recurrence Regulatory T-Lymphocyte Reporter Reporting Research Research Personnel Role Signal Transduction Site Source System T cell differentiation T memory cell T-Lymphocyte Tamoxifen Testing Th2 Cells Therapeutic Tissues Work allergic airway disease allergic airway inflammation antigen-specific T cells chemokine chemokine receptor conditional knockout cytokine effector T cell imprint in vivo mouse model novel novel therapeutic intervention receptor therapeutic target tool

项目摘要

PROJECT ABSTRACT Defining how allergen-specific, memory Th2 cells develop has the potential to change our therapeutic approach to allergic asthma, the most common asthma subtype. Th2 cells are a dominant source of type 2 cytokines IL-4, IL-5, and IL-13 that orchestrate allergic inflammation in murine models and humans with allergic asthma. In addition, allergen-specific, memory Th2 cells persist in vivo, driving recurrent allergic inflammation upon allergen re-exposure. We recently showed that tissue-resident memory Th2 cells (Th2 Trm) that durably persist in the lungs are a transcriptionally distinct memory Th2 cell subset that is critical for orchestrating recurrent allergic airway inflammation (Rahimi et al., Journal of Experimental Medicine, 2020). The objective of this proposal is to define novel mechanisms regulating the development of Th2 Trm in a murine model of allergic asthma. In the lungs, effector T cells require interactions with antigen presenting cells (APC) and cognate antigen for Trm development. In counterbalance, mechanisms limiting terminal T cell differentiation and death in peripheral tissues, such as T cell inhibitory receptors and Tregs, are required for Trm development. During allergic inflammation, the specific APC presenting antigen to effector Th2 cells and the mechanisms regulating Th2 Trm development have not been delineated. To define the APC interacting with effector Th2 cells within the lungs, we took advantage of the fact that the Th2 cell-derived cytokines IL-4 and IL-13 induce APC to express the chemokines CCL17 and CCL22, which attract Th2 cells and regulatory T cells (Tregs) via the chemokine receptor CCR4. Using a novel Ccl17/Ccl22 reporter mouse, we show that during allergic inflammation, a subpopulation of type 2 conventional dendritic cells (cDC2) specifically upregulate Ccl17 and Ccl22 expression. Furthermore, we demonstrate that the DC activation marker PD-L2 defines Ccl17/Ccl22-expressing cDC2. We hypothesize that PD-L2+ cDC2 provide unique signals, including CCL17 and CCL22, that regulate Th2 cell activation and Th2 Trm development. We further hypothesize CCR4 expression in both Th2 cells and Tregs regulates the development of Th2 Trm. In this application, we propose to develop 2 novel murine models to define cDC2-Th2 cell interactions within the lungs in vivo. Specifically, we propose to develop PD-L2+ cDC reporter/deleter mice (Aim 1) and Ccr4 flox mice (Aim 2). We delineate a research plan to address fundamental biology concerning cDC2-Th2 cell crosstalk regulating allergic immunity and the development of Th2 Trm in vivo in a model of allergic asthma. The goal of this R03 award is to assist my lab in building new experimental tools to extend work performed during my K08 award and position me to become an independent, R01-funded investigator with expertise in the mechanisms driving Th2 immunity in allergic asthma.

项目摘要定义过敏原特异性，内存Th2细胞如何改变我们的治疗方法对于过敏性哮喘，是最常见的哮喘亚型。 Th2细胞是2型细胞因子IL-4的主要来源， IL-5和IL-13在患有过敏性哮喘的鼠模型和人类中编排过敏性炎症。在另外，过敏原特异性，内存Th2细胞在体内持续存在，在过敏原上驱动反复过敏性炎症重新暴露。我们最近表明，居住的记忆Th2细胞（Th2 TRM）持久地存在于肺是一种转录不同的记忆Th2细胞子集，对于编排复发性过敏至关重要气道炎症（Rahimi等，《实验医学杂志》，2020年）。该提议的目的是定义在过敏性哮喘的鼠模型中调节Th2 TRM发展的新型机制。在肺，效应T细胞需要与抗原呈递细胞（APC）相互作用，并为TRM的同源抗原发展。在平衡中，机制限制了终末T细胞分化和外围死亡 TRM发育需要组织，例如T细胞抑制受体和TREG。在过敏性期间炎症，特定的APC呈现抗原对效应Th2细胞的抗原和调节Th2 TRM的机制发展尚未划定。为了定义与肺内效应Th2细胞相互作用的APC，我们利用了TH2细胞衍生的细胞因子IL-4和IL-13诱导APC表达APC的事实趋化因子CCL17和CCL22，它们通过趋化因子受体吸引Th2细胞和调节性T细胞（Treg） CCR4。使用新型的CCL17/CCL22报告鼠标，我们表明在过敏性炎症期间，亚种群 2型常规树突状细胞（CDC2）特异性上调CCL17和CCL22表达。此外，我们证明DC激活标记PD-L2定义了表达CCL22的CDC2。我们假设 PD-L2+ CDC2提供了独特的信号，包括CCL17和CCL22，可调节Th2细胞激活和 TH2 TRM开发。我们进一步假设在Th2细胞和Tregs中的CCR4表达都调节了 TH2 TRM的开发。在此应用中，我们建议开发2种新型鼠模型来定义CDC2-TH2 体内肺内的细胞相互作用。具体而言，我们建议开发PD-L2+ CDC报告基因/DELETER小鼠（AIM 1）和CCR4 Flox小鼠（AIM 2）。我们描述了一项研究计划，以解决有关的基本生物学 Cdc2-Th2细胞串扰调节过敏性免疫和体内Th2 TRM的发展过敏性哮喘。该R03奖的目标是协助我的实验室建立新的实验工具以扩展工作在我的K08奖中表演，并使我成为一名独立的R01资助的调查员在推动过敏性哮喘中驱动Th2免疫力的机制方面的专业知识。