Lung-resident antibacterial heterotypic immunity

肺驻留抗菌异型免疫

基本信息

批准号：
9927559
负责人：
JOSEPH P MIZGERD
金额：
$ 48.72万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927559
关键词：
Address Adult Alveolar Anatomy Anti-Bacterial Agents Antigen Presentation Antigen Presentation Pathway Biology Blocking Antibodies CD4 Positive T Lymphocytes CD40 Antigens Cell Line Cells Cellular biology Child Color Data Deposition Elements Epithelial Epithelial Cells Epithelium Fostering Future Gene Expression Profiling Genes Immune Immunity Immunofluorescence Immunologic Immunologics Immunology Infection Inflammatory Inhalation Kinetics Light Lobe Lower respiratory tract structure Lung Lymphocyte Microbe Microscopy Molecular Mus PD-L1 blockade Pattern Physiological Physiology Pneumococcal Pneumonia Pneumonia Resolution Respiratory Tract Infections Role Signal Transduction Structure Structure of parenchyma of lung Supporting Cell T memory cell T-Lymphocyte TNFRSF5 gene Testing Tissues Transgenes Type II Epithelial Receptor Cell adaptive immune response adaptive immunity alveolar epithelium antimicrobial cell growth regulation cell type conditional mutant immune resistance immunoreaction insight lung injury morphometry novel prevent programmed cell death ligand 1 respiratory segregation transcriptome sequencing

项目摘要

Abstract The proposed studies will elucidate cellular and molecular mechanisms that organize the activities, fate, and tissue localizations of CD4+ T cells in the lungs. CD4+ T cells are instructed by antigen presentation from MHC-II and costimulatory or checkpoint molecules. Our preliminary data reveal that MHC-II is widely expressed by lung epithelial cells, and dynamically regulated during and after resolution of pneumococcal pneumonia. Furthermore, we observe that distinct sub-types of lung epithelial cells express different patterns of costimulatory and checkpoint molecules. We propose that epithelial cell MHC-II pairs with cell-type-specific expression of costimulatory and checkpoint molecules to appropriately instruct CD4+ T cells, localizing CD4+ T cell activities and all aspects of adaptive immunity that depend on lung CD4+ T cells near more forgiving regions (conducting airways) and away from more fragile and demanding elements (alveoli), to increase immune resistance while diminishing lung injury. Our central hypothesis is that MHC-II on the lung epithelium drives adaptive immunity toward the conducting airways and away from the alveoli, to be tested by pursuing the following specific aims: (1) Test the hypothesis that pulmonary epithelial cells direct the anatomical segregation of CD4+ T cells in the lung. This will be accomplished using multiple microscopy approaches to document the regional kinetics and epithelial interactions of CD4+ cell expansion and contraction during and after pneumonia, RNAseq of epithelial cells that are bright vs. dim for MHC-II, and conditional mutation of MHC-II throughout all the lung epithelium. (2) Test the hypothesis that alveolar epithelial type II cells use MHC- II plus PD-L1 to limit inflammatory lung injury. This will be accomplished using PD-L1 blockade, conditional mutation of MHC-II in alveolar epithelial type II cells, and RNAseq of disparate classes of type II cells with distinct patterns of MHC-II and checkpoint molecules. (3) Test the hypothesis that airway club cells and multiciliated cells use MHC-II plus CD40 to bolster antimicrobial defense. This will be accomplished using conditional mutation of MHC-II or of CD40 in both club cells and multiciliated cells. Altogether, the studies will reveal whether and how lung epithelial cells orchestrate CD4+ T cell activities during pneumonia and determine the TRM cell niche after resolution of infection. Results will identify naturally acquired immune mechanisms that prevent pneumonia in older children and young healthy adults, provide insight into antigen presentation pathways in the lung, and elucidate roles of checkpoint and costimulatory molecules in directing lung CD4+ T cell biology.

抽象的拟议的研究将阐明组织活动、命运和生命的细胞和分子机制。 CD4+ T 细胞在肺部的组织定位。 CD4+ T 细胞受抗原呈递的指导 MHC-II 和共刺激或检查点分子。我们的初步数据显示 MHC-II 广泛由肺上皮细胞表达，并在肺炎球菌消退期间和消退后动态调节肺炎。此外，我们观察到肺上皮细胞的不同亚型表达不同的模式共刺激和检查点分子。我们认为上皮细胞 MHC-II 与细胞类型特异性配对表达共刺激和检查点分子以适当指导 CD4+ T 细胞，定位 CD4+ T 依赖于肺 CD4+ T 细胞的细胞活动和适应性免疫的各个方面几乎更加宽容区域（传导气道）并远离更脆弱和要求更高的元素（肺泡），以增加免疫抵抗力，同时减少肺损伤。我们的中心假设是肺上皮细胞上的 MHC-II 驱动适应性免疫朝向传导气道并远离肺泡，通过追求来测试具体目标如下：（1）检验肺上皮细胞指导解剖学的假设肺中 CD4+ T 细胞的分离。这将通过使用多种显微镜方法来完成记录 CD4+ 细胞扩张和收缩期间的区域动力学和上皮相互作用肺炎后，上皮细胞的 MHC-II 明亮与暗淡的 RNAseq 以及条件突变 MHC-II 遍布整个肺上皮。 (2) 检验肺泡上皮II型细胞使用MHC-的假设 II 加 PD-L1 以限制炎症性肺损伤。这将通过 PD-L1 封锁来完成，有条件肺泡上皮 II 型细胞中 MHC-II 的突变，以及不同类别 II 型细胞的 RNAseq MHC-II 和检查点分子的不同模式。 (3) 检验气道俱乐部细胞和多纤毛细胞使用 MHC-II 和 CD40 来增强抗菌防御。这将通过使用来完成俱乐部细胞和多纤毛细胞中 MHC-II 或 CD40 的条件突变。总而言之，这些研究将揭示肺上皮细胞在肺炎和肺炎期间是否以及如何协调 CD4+ T 细胞的活动感染消退后确定 TRM 细胞生态位。结果将识别自然获得性免疫预防年龄较大儿童和年轻健康成年人肺炎的机制，提供对抗原的深入了解肺部的表达途径，并阐明检查点和共刺激分子在指导中的作用肺 CD4+ T 细胞生物学。