Defining group 2 innate lymphoid cell lung niches

定义第 2 组先天淋巴细胞肺生态位

基本信息

批准号：
10241240
负责人：
Ari B Molofsky
金额：
$ 51.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241240
关键词：
3-Dimensional AREG gene Adult Allergic Allergic Disease Allergic inflammation Anatomy Automobile Driving Cell Survival Cell physiology Cells Child Clinical Trials Coculture Techniques Cues Cytokine Signaling Data Development Disease model Elements Epithelial Cells Extrinsic asthma Fibroblasts Future Genetic study Goals Helminths Human Genetics Imaging Techniques Immune Immune response Immunity Impairment In Vitro Inflammation Interleukin-13 Interleukins LIF gene Life Lung Lung Inflammation Lung diseases Lung infections Lymphocyte Lymphoid Lymphoid Cell Lymphoid Tissue Memory Mesenchymal Microscopy Modeling Molecular Mus Pathologic Pathway interactions Perinatal Predisposition Production Pyroglyphidae Recurrence Reporter Risk Factors Role Shapes Signal Transduction Source Stromal Cells TSLP gene Testing Th2 Cells Three-Dimensional Imaging Tissues Transgenic Organisms Work base cell type chronic inflammatory disease chronic inflammatory lung disease clinically relevant cytokine helminth infection insight lung development mouse model new therapeutic target novel perinatal development postnatal postnatal development postnatal period recruit tool transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract Group 2 innate lymphoid cells (ILC2s) are tissue-resident lymphocytes with emerging roles in tissue development, remodeling, and allergic disease. In the lung, ILC2s are key instigators of allergic asthma, yet little is known about where ILC2s reside and how stromal interactions shape ILC2 development and function. We have found that lung ILC2s reside in specific perivascular ‘niches’, where they intimately associate with a mesenchymal cell subset that expresses the cytokines IL-33 and TSLP. The goal of this proposal is to rigorously investigate the role and cross-talk of these ‘niche’ mesenchymal cells on ILC2 developmental localization, function, and induction of type 2 immune responses. Based on our preliminary data, we propose that niche perivascular mesenchymal cells impact ILC2 localization and function via the production of known cytokine signals, including IL-33 and TSLP, as well as other novel pathways, providing a nidus for adaptive Th2 immune responses. During inflammation, ILC2s cooperate with Th2 tissue-resident memory cells to cross- regulate mesenchymal cell function and cytokine production. In Aim One, we will define how adult lung ILC2 ‘niche-associated’ mesenchymal cells impact ILC2 activation and induction of adaptive type 2 immune responses. Global deletion of niche mesenchymal cells impaired lung type 2 immune responses, and we predict that cytokines such as IL-33 and TSLP, as well as other unknown factors, contribute to the activation of ILC2 and the type 2 immune response. In Aim Two, we will characterize the stromal cells and signals that govern the postnatal, developing ILC2 niche. Our preliminary data indicate the earliest ILC2 interact with and require mesenchymal perivascular niche cells for optimal expansion. We will test the development of these perivascular niches and their contribution to ILC2 localization and function in perinatal life, and how allergic challenges in this period alter the developing niche. In Aim three, we will explore how ILC2 and tissue Th2 cells cross-regulate niche mesenchymal cells. We have found that both ILC2, Th2, and IL-33 expressing mesenchymal niche cells expand during helminth infection, and ILC2 are required for optimal expansion and IL-33 expression by mesenchymal niche cells. Here we will test how ILC2-derived cytokines impact mesenchymal niche function during both perinatal development and adult immune challenge. We expect that signals from ILC2 dynamically regulate niche mesenchymal cell function and IL-33 expression to cause long- lasting changes in tissue immune tone and predisposition towards subsequent allergic asthma. Together, we use novel 3D imaging techniques, RNA-sequencing, and transgenic tools to answer a critical and unknown question: how are ILC2 locally regulated at their lung niches? We anticipate these studies will have fundamental implications for the control of ILC2 and type 2 allergic immunity in allergic asthma, and yield insight into how ILC2 impact both beneficial and pathologic type 2 immune responses in the lung.

项目摘要/摘要第2组先天淋巴样细胞（ILC2S）是组织在组织中起作用的组织淋巴细胞发育，重塑和过敏性疾病。在肺中，ILC2是过敏性哮喘的关键煽动者，但关于ILC2居住的地方以及基质相互作用如何塑造ILC2的发展和功能知之甚少。我们发现肺ILC2居住在特定的周围“壁ches”中，它们与A紧密相关表达细胞因子IL-33和TSLP的间充质细胞子集。该提议的目的是严格研究这些“利基”间充质细胞在ILC2发育中的作用和串扰 2型免疫复杂的定位，功能和诱导。根据我们的初步数据，我们提出了小众周围间充质细胞通过生产已知细胞因子信号，包括IL-33和TSLP，以及其他新型途径，为自适应提供了Nidus TH2免疫调查。在炎症期间，ILC2与Th2组织居住的记忆细胞合作以交叉调节间充质细胞功能和细胞因子的产生。在目标中，我们将定义成人肺ILC2的方式 “利基相关”的间充质细胞影响ILC2激活和自适应2型免疫诱导回答。利基间充质细胞的全球缺失受损2型肺部免疫血液，我们预测IL-33和TSLP等细胞因子以及其他未知因素有助于激活 ILC2和2型免疫响应。在目标两个中，我们将表征基质细胞和信号管理产后，发展ILC2利基市场。我们的初步数据表明最早的ILC2与和需要间充质周围的细胞细胞才能最佳膨胀。我们将测试这些开发血管周围壁ni及其对ILC2定位和在围产期生命中功能的贡献，以及如何过敏在此期间，挑战改变了发展中的利基市场。在AIM三中，我们将探讨ILC2和组织TH2细胞如何交叉调节的壁层间充质细胞。我们发现ILC2，TH2和IL-33表达间充质细胞在蠕虫感染期间膨胀，最佳膨胀和ILC2是必需的间充质细胞的IL-33表达。在这里，我们将测试ILC2衍生的细胞因子如何影响围产期发育和成人免疫挑战期间的间充质利基功能。我们期望这一点来自ILC2的信号动态调节了间充质细胞功能，IL-33表达引起长期组织免疫张力的持久变化和对随后的过敏性哮喘的倾向。在一起，我们使用新颖的3D成像技术，RNA测序和转基因工具来回答关键和未知的问题：ILC2在其肺壁ches中如何局部调节？我们预计这些研究将会有在过敏性哮喘中控制ILC2和2型过敏性免疫的基本意义和产量深入了解ILC2如何影响肺中的有益和病理2型免疫调查。