Recognition of microbes by NKT cells at the lung mucosal surface

描述（由申请人提供）：该申请涉及广泛的挑战领域（04）临床研究，以及特定的挑战主题，04- ai -101：开发新方法并解决粘膜免疫学中的关键问题。该项目的长期目标是了解自然杀伤T细胞（NKT）如何识别和响应呼吸道粘膜中的微生物。我们和其他人之前已经表明，肺中的NKT细胞在气道炎症和哮喘的发展中起着关键作用。此外，我们已经证明，细菌鞘单胞菌的糖脂可以直接激活小鼠肺NKT细胞，诱导气道炎症和气道高反应性（AHR），这是哮喘的主要特征。这些结果表明，肺粘膜中的NKT细胞可能对进入肺的其他微生物产生反应，并且NKT细胞可能在调节肺粘膜免疫反应中发挥先前未被怀疑的关键作用。尽管大多数哮喘患者的肺部被认为是无菌的，但我们有强有力的和令人惊讶的初步数据表明，高度多样化的复杂细菌联合体实际上存在于很大一部分哮喘患者的肺部，这是用一种极其敏感的新型非培养的16S rRNA PhyloChip微阵列方法检测到的。存在的微生物包括肺炎链球菌，以及以前没有通过基于培养的技术检测到的细菌，如鞘脂单胞菌，它表达可以激活NKT细胞的糖脂。基于这些研究，我们认为微生物在慢性肺部炎症性疾病患者的气道黏膜中比以前认识到的要常见得多。此外，虽然只有少数微生物已知可以激活NKT细胞，但基于强有力的初步数据，我们假设许多肺部微生物，包括肺炎链球菌、新绿伯克霍尔德菌、少移动鞘氨单胞菌和烟曲霉，表达可以激活NKT细胞的糖脂，从而导致先天性和适应性粘膜免疫反应。因此，我们认为宿主对支气管内粘膜中常见的以及以前未被识别的微生物的反应可引发气道中的慢性疾病。在本项目中，我们拟从肺炎链球菌、cenocepacia芽孢杆菌和烟状芽孢杆菌中鉴定能直接激活NKT细胞的糖脂。这些研究将证明存在于肺部的微生物能够激活NKT细胞并诱导AHR、炎症和哮喘的特定机制。我们的研究将极大地扩展对呼吸道粘膜中存在的微生物产生的免疫反应类型的基本理解，以及这些反应如何导致慢性肺部疾病（如哮喘）的发展。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research, and the specific Challenge Topic, 04-AI-101: Develop novel methods and address key questions in mucosal immunology. The long-term goal of this project is to understand how natural killer T (NKT) cells recognize and respond to microorganisms in the respiratory mucosa. We and others have previously shown that NKT cells in the lungs play a critical role in the development of airway inflammation and asthma. In addition, we have shown that glycolipids from the bacterial species Sphingomonas can directly activate pulmonary NKT cells in mice and induce airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. These results suggest that NKT cells in the lung mucosa may respond to other microorganisms that enter the lung, and that NKT cells could play a previously unsuspected critical role in regulating pulmonary mucosal immune responses. Although the lungs of most patients with asthma are thought to be sterile, we have strong and surprising preliminary data indicating that a highly diverse complex bacterial consortia are in fact present in the lungs of a large fraction of patients with asthma, as detected with an extremely sensitive, novel non-culture based 16S rRNA PhyloChip microarray method. The microorganisms present include Streptococcus pneumoniae, as well as bacteria not previously detected by culture-based techniques, such as Sphingomonas paucimobilis, which express glycolipids that can activate NKT cells. Based on these studies, we suggest that microorganisms are much more common in the airway mucosa of patients with chronic pulmonary inflammatory diseases than previously recognized. Furthermore, while only a few microorganisms are known to activate NKT cells, based on strong preliminary data, we hypothesize that many pulmonary microorganisms, including S. pneumoniae, Burkholderia cenocepacia, Sphingomonas paucimobilis and Aspergillus fumigatus express glycolipids that can activate NKT cells, resulting in innate and adaptive mucosal immune responses. We therefore believe that host responses to common, as well as previously unrecognized, microorganisms in the endobronchial mucosa can trigger chronic diseases in the airways. In this project, we propose to identify glycolipids from S. pneumoniae, B. cenocepacia, and A. fumigatus that can directly activate NKT cells. These studies will demonstrate a specific mechanism by which microorganisms present in the lungs can activate NKT cells and induce AHR, inflammation and asthma. Our studies will greatly expand the fundamental understanding of the types of immune responses that develop against microorganisms present in the respiratory mucosa, and how these responses result in the development of chronic lung diseases, such as asthma. PUBLIC HEALTH RELEVANCE: The results of these studies will have a direct impact on our fundamental understanding of the immune responses that occur in the respiratory mucosa. We propose to understand how a novel cell type, called natural killer T cells, fundamentally regulates innate and adaptive immunity to respiratory microorganisms. These studies will complement additional studies that we are performing, supported by other grants and using a novel, highly sensitive non-culture molecular method, to define the microorganisms that are present in the lungs of patients with chronic lung disease, such as asthma. These results will provide a much greater appreciation and understanding of mucosal immunity to microorganisms present in the respiratory tract, and how these immune responses lead to respiratory inflammation and to the development of chronic lung diseases, such as asthma and COPD.