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

• 批准号: 10670871
• 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
• 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/10670871
• 关键词: Address; Allergens; Allergic; Allergic Disease; Allergic inflammation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Asthma; Automobile Driving; Award; Biology; Breeding; 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; LoxP-flanked allele; 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

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 确定过敏原特异性记忆性Th 2细胞如何发育有可能改变我们的治疗方法 过敏性哮喘，最常见的哮喘亚型。Th 2细胞是2型细胞因子IL-4的主要来源， IL-5和IL-13在小鼠模型和患有过敏性哮喘的人中协调过敏性炎症。在 此外，过敏原特异性记忆性Th 2细胞在体内持续存在，在过敏原刺激下驱动复发性过敏性炎症 再曝光我们最近发现，持久存在于组织中的组织驻留记忆性Th 2细胞（Th 2 Trm）， 肺是转录上不同的记忆性Th 2细胞亚群，其对于协调复发性过敏反应至关重要。 气道炎症（Rahimi等人，Journal of Experimental Medicine，2020）。本提案的目的是 确定调节过敏性哮喘小鼠模型中Th 2 Trm发展的新机制。在 在肺中，效应T细胞需要与抗原呈递细胞（APC）和Trm的同源抗原相互作用 发展在平衡中，外周血中限制终末T细胞分化和死亡的机制 组织，如T细胞抑制性受体和T细胞，是Trm发育所必需的。过敏期间 炎症、特异性APC提呈抗原至效应性Th 2细胞及调节Th 2 Trm的机制 发展尚未确定。为了确定APC与肺内效应Th 2细胞的相互作用， 我们利用Th 2细胞衍生的细胞因子IL-4和IL-13诱导APC表达IL-4和IL-13的事实。 趋化因子CCL 17和CCL 22，通过趋化因子受体吸引Th 2细胞和调节性T细胞（TCL 4） CCR 4。使用一种新的Ccl 17/Ccl 22报告小鼠，我们发现在过敏性炎症过程中， 2型常规树突状细胞（cDC 2）特异性上调Ccl 17和Ccl 22表达。此外，委员会认为， 我们证明了DC活化标记物PD-L2定义了表达Ccl 17/Ccl 22的cDC 2。我们假设 PD-L2+ cDC 2提供独特的信号，包括CCL 17和CCL 22，其调节Th 2细胞活化， Th 2 Trm开发。我们进一步假设CCR 4在Th 2细胞中的表达和TcR调节Th 2细胞的增殖。 Th 2 Trm的发展在本申请中，我们提出开发2种新的小鼠模型来定义cDC 2-Th 2 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/删除小鼠， (Aim 1）和Ccr 4 flox小鼠（Aim 2）。我们描绘了一个研究计划，以解决基础生物学， CDC 2-Th 2细胞串扰调节过敏性免疫和Th 2 Trm在体内的形成 过敏性哮喘这个R 03奖的目标是帮助我的实验室建立新的实验工具，以扩展工作 在我的K 08奖期间进行，并使我成为一名独立的，R 01资助的调查员， 在过敏性哮喘中驱动Th 2免疫机制的专业知识。