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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：
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.

项目总结/摘要第2组先天性淋巴样细胞（ILC 2）是组织驻留淋巴细胞，在组织中发挥新的作用发育、重塑和过敏性疾病。在肺中，ILC 2是过敏性哮喘的关键煽动者，然而，关于ILC 2的位置以及基质相互作用如何影响ILC 2的发育和功能知之甚少。我们已经发现，肺ILC 2位于特定的血管周围“龛”中，在那里它们与肺内的细胞因子密切相关。间充质细胞亚群表达细胞因子IL-33和TSLP。本提案的目的是严格研究这些“小生境”间充质细胞在ILC 2发育中的作用和相互作用， 2型免疫应答的定位、功能和诱导。根据我们的初步数据，我们建议小生境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，以及其他新的途径，提供了一个病灶， Th 2免疫反应。在炎症过程中，ILC 2与Th 2组织驻留记忆细胞合作，调节间充质细胞功能和细胞因子产生。在目的一，我们将定义成人肺ILC 2 “小生境相关”间充质细胞影响ILC 2激活和适应性2型免疫的诱导应答小生境间充质细胞的整体缺失损害了肺2型免疫反应，我们预测细胞因子如IL-33和TSLP，以及其他未知因素，有助于激活 ILC 2和2型免疫应答。在目标二中，我们将描述基质细胞和信号，控制着出生后发育中的ILC 2生态位。我们的初步数据表明，最早的ILC 2与需要间充质血管周围小生境细胞以实现最佳扩增。我们将测试这些的发展血管周围的小生境及其对ILC 2定位和功能的贡献，以及过敏性疾病如何影响ILC 2的定位和功能。这一时期的挑战改变了发展中国家的地位。在目标三中，我们将探讨ILC 2和组织Th 2细胞如何在体内发挥作用。交叉调节小生境间充质细胞。我们已经发现ILC 2、Th 2和IL-33的表达均与IL-10的表达有关。间充质小生境细胞在蠕虫感染期间扩增，ILC 2是最佳扩增所需的，间充质小生境细胞的IL-33表达。在这里，我们将测试ILC 2衍生的细胞因子如何影响间充质生态位功能在围产期发育和成人免疫挑战。我们预计来自ILC 2的信号动态调节小生境间充质细胞功能和IL-33表达，组织免疫张力的持久变化和随后过敏性哮喘的易感性。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的和未知的问题。问题：ILC 2在肺部生态位的局部调控如何？我们预计这些研究将在过敏性哮喘中控制ILC 2和2型过敏性免疫的基本意义，深入了解ILC 2如何影响肺部的有益和病理性2型免疫应答。