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：
10458150
负责人：
Ari B Molofsky
金额：
$ 11.3万
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/10458150
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.

项目概要/摘要第 2 组先天淋巴细胞 (ILC2) 是组织驻留淋巴细胞，在组织中发挥新兴作用然而，在肺部，ILC2 是过敏性哮喘的关键诱发因素。关于 ILC2 的位置以及基质相互作用如何影响 ILC2 的发育和功能，人们知之甚少。我们发现肺 ILC2 存在于特定的血管周围“壁龛”中，在那里它们与表达细胞因子 IL-33 和 TSLP 的间充质细胞亚群该提案的目标是严格研究这些“利基”间充质细胞对 ILC2 发育的作用和串扰根据我们的初步数据，我们提出了 2 型免疫反应的定位、功能和诱导。血管周围间充质细胞通过产生已知的 ILC2 定位和功能来影响 ILC2 的定位和功能。细胞因子信号，包括 IL-33 和 TSLP，以及其他新途径，为适应性提供了一个巢穴 Th2 免疫反应期间，ILC2 与 Th2 组织驻留记忆细胞合作进行交叉免疫。在目标一中，我们将定义成人肺 ILC2 的调节机制。 “利基相关”间充质细胞影响 ILC2 激活和适应性 2 型免疫的诱导微生境间充质细胞的整体缺失损害了肺 2 型免疫反应，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 型免疫反应在目标二中，我们将表征基质细胞和信号。控制出生后、发育中的 ILC2 生态位。我们的初步数据表明，ILC2 最早与 ILC2 相互作用并相互作用。需要间充质血管周围微环境细胞进行最佳扩张，我们将测试这些细胞的发育。血管周围微环境及其对 ILC2 定位和围产期功能的贡献，以及过敏如何这一时期的挑战改变了发展中的利基市场。在目标三中，我们将探讨 ILC2 和组织 Th2 细胞的关系。我们发现 ILC2、Th2 和 IL-33 均表达交叉调节。间充质微环境细胞在蠕虫感染期间扩张，并且需要 ILC2 来实现最佳扩张和间充质微环境细胞表达 IL-33 在这里，我们将测试 ILC2 衍生的细胞因子如何影响。我们预计围产期发育和成人免疫挑战期间的间充质生态位功能。来自 ILC2 的信号动态调节微环境间充质细胞功能和 IL-33 表达，从而导致长组织免疫张力的持久变化和随后过敏性哮喘的易感性，我们一起努力。使用新颖的 3D 成像技术、RNA 测序和转基因工具来回答关键的未知问题问题：我们预计这些研究将如何在肺部局部调节 ILC2？对控制过敏性哮喘中 ILC2 和 2 型过敏免疫的基本影响以及产量深入了解 ILC2 如何影响肺部的有益和病理性 2 型免疫反应。