The Origin and Role of Pulmonary ILC2 Subsets in Anti-Helminth Immunity

肺 ILC2 亚群在抗蠕虫免疫中的起源和作用

• 批准号: 10675765
• 负责人: Richard Lee Reinhardt
• 金额: $ 55.32万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675765
• 关键词: Animals; Appearance; Blocking Antibodies; Bone Marrow; CXCR4 gene; CXCR6 gene; Cell Adhesion Molecules; Cell Compartmentation; Cell Lineage; Cells; Cellular biology; Data; Dependence; Endothelium; Epithelium; Genes; Genomics; Helminths; Heterogeneity; Hookworm Infections; Human; Image; Immigration; Immune; Immune response; Immunity; Infection; Inflammatory; Integrins; Interleukin-13; Interleukin-4; Interleukin-5; Intestines; Knowledge; Lung; Lymphoid Cell; Maintenance; Maps; Mediating; Mucositis; Mucous Membrane; Mus; Nature; Persons; Phenotype; Physiological; Play; Population; Process; Productivity; Publications; Reporter; Role; Shapes; Slice; Small Intestines; Soil; Source; System; Testing; Tissues; Work; World Health Organization; cell motility; chemokine receptor; cytokine; first responder; helminth infection; in vivo; innovation; intestinal epithelium; migration; repaired; self-renewal; sphingosine 1-phosphate; stem; stem cells; transmission process

Project Summary The World Health Organization estimates that soil transmitted helminths infect 1 in 4 people worldwide. Protection or clearance of these parasitic worms requires the initiation of a type-2 immune response. Productive type-2 immunity and worm clearance are dependent on three key cytokines: interleukin (IL)-4, IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2) represent an important source of type-2 cytokines. Specifically, ILC2 cells sense damaged mucosa and act as early orchestrators anti-helminth immunity. Currently, much of our understanding regarding the role of ILC2 cells in anti-helminth immunity stems from work focused on tissue- resident ILC2 or natural ILC2 (nILC2) cells. However, we and others have recently described a second subset of migratory ILC2s, termed inflammatory ILC2, (iILC2) cells. The distinct phenotype, timing, origin, and function of these distinct ILC2 subsets suggests that iILC2 cells serve a unique role in anti-helminth immunity. The studies outlined herein will address the following critical gaps in our knowledge: 1) The origin(s) of iILC2 cells, which remains in debate. 2) How iILC2 cells transit to the lung and the extent they enter the parenchyma during infection is unknown. 3) The impact that iILC2 cells have on tissue-resident ILC2 population remains unclear, and their role in long-term protection against helminths has not been explored. The aims below will address these knowledge gaps by testing the central hypothesis that migratory iILC2 cells, originating from small intestine or bone marrow precursors, acquire an nILC2 phenotype upon entry into the lung and contribute significantly to barrier immunity after repeated helminth infection. Aim 1: Determine iILC2 origin and tissue heterogeneity during helminth infection. Aim 2: Elucidate the mechanism of iILC2 migration and diapedesis into the lung. Aim 3: Determine the extent that iILC2 cells contribute to the tissue-resident ILC2 pool after sequential N. brasiliensis exposure. These aims are both innovative in concept (by challenging the current dogma surrounding iILC2 cells) and approach (by using unique reporter mice and genomic systems to track the fate and function of iILC2 cells). This proposal is significant because understanding of the origin of iILC2 cells, how they egress and migrate to inflamed mucosa, and their contribution to the long-term tissue-resident ILC2 population in the lung significantly advances our understanding of ILC2 biology. Filling these key gaps in our knowledge will establish the role of iILC2 cells as both critical first responders to helminth infection and also identify the mechanisms contributing to their role in long-term barrier maintenance and integrity.

项目概要 世界卫生组织估计，全世界有四分之一的人感染土壤传播的蠕虫。 保护或清除这些寄生虫需要启动 2 型免疫反应。富有成效 2 型免疫和蠕虫清除依赖于三种关键细胞因子：白细胞介素 (IL)-4、IL-5 和 IL-13。 第 2 组先天淋巴细胞 (ILC2) 是 2 型细胞因子的重要来源。具体来说，ILC2细胞 感知受损的粘膜并充当抗蠕虫免疫的早期协调者。目前，我们的大部分 关于 ILC2 细胞在抗蠕虫免疫中的作用的理解源于专注于组织的工作 常驻 ILC2 或天然 ILC2 (nILC2) 细胞。然而，我们和其他人最近描述了第二个子集 迁移性 ILC2 细胞，称为炎症 ILC2 (iILC2) 细胞。独特的表型、时间、起源和功能 这些不同的 ILC2 子集表明 iILC2 细胞在抗蠕虫免疫中发挥着独特的作用。 本文概述的研究将解决我们知识中的以下关键空白：1） iILC2 细胞，仍存在争议。 2）iILC2细胞如何转运至肺部以及进入肺部的程度 感染期间的实质未知。 3) iILC2细胞对组织驻留ILC2群体的影响 目前尚不清楚，并且尚未探讨它们在长期预防蠕虫方面的作用。目标如下 将通过测试中心假设来解决这些知识差距，即迁移性 iILC2 细胞源自 小肠或骨髓前体，在进入肺部后获得 nILC2 表型并贡献 反复感染蠕虫后，对屏障免疫有显着影响。目标 1：确定 iILC2 起源和组织 蠕虫感染期间的异质性。目标 2：阐明 iILC2 迁移和渗出的机制 肺。目标 3：确定 iILC2 细胞在序贯后对组织驻留 ILC2 库的贡献程度 巴西猪笼草暴露。这些目标在概念上都是创新的（通过挑战当前的教条） 围绕 iILC2 细胞）和方法（通过使用独特的报告小鼠和基因组系统来追踪命运和 iILC2 细胞的功能）。该提案意义重大，因为了解 iILC2 细胞的起源、如何 它们流出并迁移到发炎的粘膜，以及它们对长期组织驻留的 ILC2 的贡献 肺中的群体显着增进了我们对 ILC2 生物学的理解。填补我们的这些关键空白 这些知识将确定 iILC2 细胞作为蠕虫感染的关键第一反应者和 确定有助于其在长期屏障维护和完整性中发挥作用的机制。