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 确定过敏原特异的记忆性Th2细胞如何发展有可能改变我们的治疗方法 以过敏性哮喘为最常见的哮喘亚型。Th2细胞是2型细胞因子IL-4的主要来源， IL-5和IL-13在过敏性哮喘小鼠模型和人类中协调过敏性炎症。在……里面 此外，过敏原特异的记忆性Th2细胞在体内持续存在，导致过敏原引起反复的过敏性炎症 重新曝光。我们最近发现，组织驻留的Th2细胞(Th2Trm)持续存在于 肺是一种转录上不同的记忆Th2细胞亚群，对协调复发性过敏至关重要 呼吸道炎症(Rahimi等人，《实验医学杂志》，2020年)。这项提议的目标是 目的：确定在过敏性哮喘小鼠模型中调节Th2Trm发展的新机制。在 肺，效应性T细胞需要与抗原提呈细胞(APC)和Trm同源抗原相互作用 发展。在平衡中，限制外周T细胞终末分化和死亡的机制 T细胞抑制受体和Tregs等组织是Trm发育所必需的。在过敏期间 炎症、特异性APC递呈Th2细胞抗原及其调节Th2 Trm的机制 发展还没有被描绘出来。为了定义与肺内效应器Th2细胞相互作用的APC， 我们利用Th2细胞衍生的细胞因子IL-4和IL-13诱导APC表达 趋化因子CCL17和CCL22，通过趋化因子受体吸引Th2细胞和调节性T细胞(Treg) CCR4.使用一只新的Ccl17/CCL22报告小鼠，我们发现在过敏性炎症期间，一个亚群 2型常规树突状细胞(CDC2)特异性上调Ccl17和CCL22的表达。此外， 我们证明DC激活标记PD-L2定义了表达Ccl17/CCL22的cDC2。我们假设 PD-L2+cDC2提供独特的信号，包括CCL17和CCL22，调节Th2细胞的激活和 T2Trm的发展。我们进一步假设CCR4在Th2细胞和Tregs中的表达调节 Th2Trm的研究进展在这个应用中，我们建议建立两个新的小鼠模型来定义cDC2-Th2 活体内肺内细胞的相互作用。具体地说，我们建议开发PD-L2+CDC报告/缺失小鼠 (目标1)和CCR4 FLOX小鼠(目标2)。我们描绘了一项研究计划，以解决基础生物学关于 CDC2-Th2细胞串扰调节变态反应免疫及体内Th2Trm的形成 过敏性哮喘。R03奖的目标是帮助我的实验室构建新的实验工具，以扩展工作 在我的K08奖项期间完成，并将我定位为一名独立的、由R01资助的调查员 过敏性哮喘患者Th2免疫机制方面的专业知识。