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: 10044123
• 负责人: Yuefeng Huang
• 金额: $ 39.75万
• 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/10044123
• 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; Distal; Drug Screening; Drug Targeting; Drug usage; Extrinsic asthma; Flow Cytometry; Goals; Homeostasis; Host Defense; Human; Immune; Immune system; Immunologics; Immunology; Infection; Inflammation; Inflammatory; Intestines; Knowledge; Lead; Lung; Lymphoid Cell; Mediating; Metabolic; Metabolic Diseases; Molecular; Molecular Biology; Mus; Organ; Parasitic infection; Play; Population; 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; imaging genetics; 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.

项目摘要 先天性淋巴样细胞（inate lymphoid cells，ILC）是脊椎动物免疫系统的重要组成部分。它们共享一个 骨髓中常见的淋巴祖细胞，具有T和B细胞，但缺乏抗原特异性受体。ILC本地化 在小鼠和人的许多组织中，但在屏障表面如肺、肠和皮肤中富集， 它们直接响应从发炎或受伤组织释放的“alarmin”细胞因子信号。通过产生 ILC是一系列“效应”细胞因子，启动并放大下游免疫反应，因此被认为是 在宿主防御中起关键作用的早期保护者。越来越多的证据表明ILC在组织中也发挥着重要作用 重塑、代谢稳态、炎症和自身免疫性疾病。我的研究愿景是了解 ILC活化、迁移的生物学原理和分子基础及其免疫功能。 ILC通常被认为是组织驻留细胞，即使在感染期间也不循环。但这 ILC的主要概念已经完全改变了我最近发现的一个新的ILC人口，称为 炎症或诱导的ILC 2，其在蠕虫感染期间从肠道迁移到肺。这些调查结果 建立一个新的ILC生物学范式：虽然ILC，或ILC 2在最低限度，主要是组织驻留在 在稳态下，它们在感染期间变得移动的，并有助于远端免疫保护。有了这个新 在这一范式下，国际法委员会的许多基本问题有待回答。在拟议的五年项目中，我们的目标是 回答几个问题：1）马槟榔衍生的ILC 2调节哮喘吗？我们假设肠道的重新定位- 在寄生虫感染过程中，衍生的iILC 2进入肺通过赋予“先天性” 对哮喘过敏原的耐受性2)微生物群调节ILC 2激活和迁移吗？我们 假设肠道微生物群对于精氨酸诱导ILC 2应答和肠道细菌是必需的- 衍生的代谢物提供了促进ILC 2活化和随后的器官间 贩卖人口3)现有的靶向T细胞的药物是否有能力调节ILC功能？我们将执行 一个筛选试验，以确定这些候选药物通过使用基因报告系统，我们已经产生。 成功完成拟议的研究将导致对分子生物学的基本理解。 ILC 2活化、ILC 2迁移、ILC 2重新定位介导的抗 过敏性哮喘和微生物群-ILC 2相互作用。获得的知识将有助于发展 哮喘和其他炎症及感染性疾病的新治疗方法。现有药物 筛查将加强对临床药物使用的重新考虑。将采用多学科方法 包括高参数流式细胞术、单细胞（sc）RNA-Seq、scATAC-Seq、多重3D组织成像 和遗传小鼠模型。这是一个集免疫细胞生物学、分子生物学、系统 免疫学和宿主-病原体相互作用。哥伦比亚大学医学中心提供了大量的研究 资源和巨大的合作机会，这将使之成为可能。