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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：
10677246
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/10677246
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 diseases Lung infections Lymphocyte Lymphoid Lymphoid Cell Lymphoid Tissue Memory Mesenchymal Microscopy Modeling Molecular Mus Pathologic Pathway interactions Perinatal Predisposition Production Pulmonary Inflammation 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/摘要第二组先天淋巴样细胞(ILC2s)是一种驻留在组织中的淋巴细胞，在组织中具有新的作用发展、重塑和过敏性疾病。在肺部，ILC2是过敏性哮喘的关键煽动者，但对于ILC2在哪里存在以及间质相互作用如何影响ILC2的发育和功能，人们知之甚少。我们发现肺中的ILC2存在于特定的血管周围“缝隙”中，在那里它们与一种间充质细胞亚群，表达细胞因子IL-33和TSLP。这项提议的目标是严格研究这些“小生境”间充质细胞在ILC2发育中的作用和相互作用 2型免疫反应的定位、功能和诱导。根据我们的初步数据，我们建议利基血管周围间充质细胞通过产生已知的细胞因子信号，包括IL-33和TSLP，以及其他新的信号通路，为适应性 Th2免疫反应。在炎症期间，ILC2与Th2组织驻留的记忆细胞合作，交叉- 调节间充质细胞功能和细胞因子的产生。在第一个目标中，我们将定义成人肺ILC2 “小生境相关”间充质细胞影响ILC2的激活和诱导适应性2型免疫回应。NICE间充质细胞的全局缺失损害了肺2型免疫反应预测细胞因子如IL-33和TSLP，以及其他未知因素，有助于激活 ILC2和2型免疫反应。在第二个目标中，我们将描述基质细胞和信号管理出生后，发展ILC2利基。我们的初步数据表明，最早的ILC2与需要间充质血管周围壁龛细胞才能获得最佳的扩增。我们将测试这些工具的开发情况血管周围的壁龛及其对ILC2在围产期的定位和功能的贡献，以及如何过敏这一时期的挑战改变了发展中的利基市场。在第三个目标中，我们将探索ILC2和组织Th2细胞如何交叉调节壁龛间充质细胞。我们发现ILC2、Th2和IL-33都表达间充质龛细胞在蠕虫感染期间扩张，ILC2是最佳扩增和间充质细胞巢细胞表达IL-33。在这里，我们将测试ILC2衍生的细胞因子如何影响间充质生态位在围产期发育和成人免疫挑战中的作用。我们期待着来自ILC2的信号动态调节龛间充质细胞功能和IL-33的表达，导致长时间的组织免疫张力和随后的过敏性哮喘的易感性的持久变化。在一起，我们使用新的3D成像技术、RNA测序和转基因工具来回答一个关键和未知的问题问：ILC2在它们的肺脏生态位上是如何受到当地监管的？我们预计这些研究将会有 ILC2和2型变态反应性免疫在变态反应性哮喘中的控制的基本意义和产量深入了解ILC2如何影响肺部有益的和病理性的2型免疫反应。