Elucidation of the regulation and function of innate lymphoid cells

阐明先天淋巴细胞的调节和功能

• 批准号: 10810088
• 负责人: Yuefeng Huang
• 金额: $ 1.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810088
• 关键词: 3-Dimensional; Academic Medical Centers; Allergens; Allergic Disease; Antigen-Antibody Complex; Antigens; Asthma; Autoimmune Diseases; B-Lymphocytes; Biological; Biological Assay; Biology; Bone Marrow; Cells; Cellular biology; Clinic; Collaborations; Common Lymphoid Progenitor; Communicable Diseases; Cytokine Signaling; Development; Disease; Distal; Drug Screening; Drug Targeting; Drug usage; Extrinsic asthma; Flow Cytometry; Genetic; Goals; Homeostasis; Host Defense; Human; Immune; Immune system; Immunologics; Immunology; Infection; Inflammation; Inflammatory; Intestines; Knowledge; Lung; Lymphoid Cell; Mediating; Metabolic; Metabolic Diseases; Molecular; Molecular Biology; Mus; Organ; Parasitic infection; Play; Population; Positioning Attribute; Regulation; Reporter Genes; Research; Resources; Role; Signal Transduction; Skin; Surface; System; T-Lymphocyte; Tissue imaging; Tissues; allergic response; asthmatic; commensal bacteria; cytokine; drug candidate; gut microbiota; helminth infection; immune function; immunoreaction; injured; interdisciplinary approach; microbiota; migration; mouse model; novel therapeutic intervention; pathogen; pathogenic bacteria; receptor; response; screening; single-cell RNA sequencing; trafficking

PROJECT SUMMARY Innate lymphoid cells or ILCs are recently characterized constitutes of vertebrate immune system. They share a common lymphoid progenitor in bone marrow with T and B cells but lack antigen-specific receptors. ILCs localize in many tissues of both mice and humans but are enriched in barrier surfaces such as lung, gut and skin, where they directly respond to ‘alarmin’ cytokine signals released from inflamed or injured tissues. By producing an array of ‘effecter’ cytokines, ILCs initiate and amplify downstream immune reactions, thus are considered to be critical early protectors in host defense. Increasing evidence indicates that ILCs also play important roles in tissue remolding, metabolic homeostasis, inflammation and autoimmune disorders. My research vison is to understand the biological principles and molecular basis of ILC activation, migration, and their immunological functions. ILCs were generally believed to be tissue-resident cells and they don’t circulate even during infection. But this major concept of ILC has been completely changed by my recent discovery of a new ILC population, termed inflammatory or induced ILC2s, which migrate from the gut to the lung during helminth infection. Those findings establish a new paradigm of ILC biology: though ILCs, or ILC2s at a minimum, are largely tissue resident in the steady state, they become mobile during infection and contribute to distal immune protection. With this new paradigm, many fundamental questions on ILCs are to be answered. In the proposed five-year project, we aim to answer a few: 1) Do intestine-derived ILC2s modulate asthma? We hypothesize that repositioning of gut- derived iILC2s to the lung during parasitic infection dampens the allergic responses by conferring ‘innate tolerance’ to stronger asthmatic allergens. 2) Does microbiota modulate ILC2 activation and migration? We hypothesize that intestinal microbiota is essential for cytokine-induced ILC2 responses and commensal bacteria- derived metabolites provide a secondary signal that facilitates ILC2 activation and subsequent inter-organ trafficking. 3) Do existing drugs that target T cells have the capability to regulate the ILC function? We will perform a screening assay to identify such candidate drugs by using a gene reporter system that we have generated. Successful completion of the proposed studies will lead to a fundamental understanding of molecular mechanisms that underlie ILC2 activation, ILC2 migration, ILC2 repositioning-mediated protection against allergic asthma, and microbiota-ILC2 interaction. The knowledge to be gained will contribute to the development of novel therapeutic approaches for asthma and other inflammatory and infectious diseases. The existing drug screening will enhance the reconsideration of drug usage in clinic. Multi-disciplinary approaches will be employed including high-parameter flow cytometry, single-cell(sc) RNA-Seq, scATAC-Seq, multiplex 3D tissue imaging and genetic mouse models. This is a research complex of immune cell biology, molecular biology, system immunology and host-pathogen interaction. Columbia University Medical Center provides enormous research resources and great opportunities for collaborations that will make it possible.

项目总结 先天淋巴样细胞是脊椎动物免疫系统的重要组成部分。他们共享一个 骨髓中有T和B细胞的常见淋巴祖细胞，但缺乏抗原特异性受体。ILC本地化 在小鼠和人类的许多组织中，但富含在肺、肠道和皮肤等屏障表面，其中 它们对炎症或损伤组织释放的细胞因子信号做出直接反应。通过生成一个 作为一系列“效应者”细胞因子，ILC启动和放大下游免疫反应，因此被认为是 寄主防御中的关键早期保护者。越来越多的证据表明，ILC在组织中也发挥着重要作用 重塑、代谢动态平衡、炎症和自身免疫性疾病。我的研究目的是了解 ILC激活、迁移的生物学原理、分子基础及其免疫功能。 ILC通常被认为是组织驻留细胞，即使在感染期间它们也不会循环。但这件事 我最近发现了一种名为ILC的新种群，这完全改变了ILC的主要概念 炎症性或诱导性ILC2，在蠕虫感染期间从肠道迁移到肺部。这些发现 建立一种新的ILC生物学范式：尽管ILC，或者至少是ILC2，主要是驻留在 在稳定状态下，它们在感染期间可以移动，有助于远端免疫保护。有了这个新的 在这一范式下，关于国际法的许多基本问题都有待回答。在拟议的五年计划中，我们的目标是 回答几个问题：1)肠道来源的ILC2调节哮喘吗？我们假设Gut的重新定位- 寄生虫感染时肺内衍生的iILC2s通过赋予先天免疫功能来抑制过敏反应 对更强的哮喘过敏原的耐受性。2)微生物区系是否调节ILC2的激活和迁移？我们 假设肠道微生物区系对细胞因子诱导的ILC2反应和共生菌- 衍生代谢物提供二次信号，促进ILC2激活和随后的器官间 贩卖人口。3)针对T细胞的现有药物是否具有调节ILC功能的能力？我们将表演 一种筛选试验，通过使用我们产生的基因报告系统来识别这样的候选药物。 成功完成拟议的研究将导致对分子的基本理解 ILC2激活、ILC2迁移、ILC2重新定位介导的保护机制 过敏性哮喘，以及微生物区系-ILC2的相互作用。将获得的知识将有助于发展 对哮喘和其他炎症性和感染性疾病的新治疗方法的研究。现有的药物 筛查将加强对临床用药的重新考虑。将采用多学科的方法。 包括高参数流式细胞术、单细胞(Sc)RNA-Seq、scATAC-Seq、多路三维组织成像 和遗传小鼠模型。这是一个免疫细胞生物学、分子生物学、系统的研究综合体。 免疫学和宿主与病原体的相互作用。哥伦比亚大学医学中心提供大量研究 使之成为可能的资源和巨大的合作机会。