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: 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
• 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

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 定义过敏原特异性记忆 Th2 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。 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小鼠模型和人类中协调过敏性炎症。在 此外，过敏原特异性记忆 Th2 细胞在体内持续存在，导致过敏原引起的反复过敏性炎症 重新曝光。我们最近发现，组织驻留记忆 Th2 细胞 (Th2 Trm) 能够持久存在于组织中。 肺部是转录上不同的记忆 Th2 细胞亚群，对于协调复发性过敏至关重要 气道炎症（Rahimi 等人，实验医学杂志，2020）。该提案的目标是 确定在过敏性哮喘小鼠模型中调节 Th2 Trm 发育的新机制。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。作为平衡，限制外周 T 细胞终末分化和死亡的机制 Trm 发育需要 T 细胞抑制性受体和 Tregs 等组织。过敏期间 炎症、向效应 Th2 细胞呈递抗原的特异性 APC 以及调节 Th2 Trm 的机制 发展尚未明确。为了定义 APC 与肺内效应 Th2 细胞的相互作用， 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 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。使用新型 Ccl17/Ccl22 报告小鼠，我们发现在过敏性炎症期间，一个亚群 2 型传统树突状细胞 (cDC2) 特异性上调 Ccl17 和 Ccl22 表达。此外， 我们证明 DC 激活标记物 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 细胞激活和 Th2 Trm 发育。我们进一步假设 Th2 细胞和 Tregs 中的 CCR4 表达调节 Th2 Trm 的发育。在此应用中，我们建议开发 2 种新型小鼠模型来定义 cDC2-Th2 体内肺内细胞相互作用。具体来说，我们建议开发 PD-L2+ cDC 报告/删除小鼠 （目标 1）和 Ccr4 flox 小鼠（目标 2）。我们制定了一项研究计划来解决有关基础生物学的问题 cDC2-Th2细胞串扰在模型中调节过敏性免疫和体内Th2 Trm的发育 过敏性哮喘。 R03 奖项的目标是协助我的实验室构建新的实验工具来扩展工作 在我的 K08 奖期间进行，使我成为一名独立的、由 R01 资助的调查员 过敏性哮喘中驱动 Th2 免疫机制的专业知识。