The role of natural killer T cells in the innate response to lung infection

自然杀伤 T 细胞在肺部感染先天反应中的作用

• 批准号: 8862370
• 负责人: MITCHELL KRONENBERG
• 金额: $ 44.25万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-05 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862370
• 关键词: 1,2-diacylglycerol; Ablation; Address; Adjuvant; Affect; Alleles; Antigens; Bacteria; Bacterial Infections; Behavior; Binding; Breathing; Cell Communication; Cell physiology; Cells; Cellular Immunology; Cessation of life; Data; Defect; Development; Diglycerides; Dose; Elements; Epithelial; Epithelial Cells; Epithelium; Family; Family member; Genes; Glycolipids; Health; Host Defense; Hour; Image; Immune; Immune response; In Situ; Infection; Inflammatory; Interferon Type II; Interleukin-17; Lead; Leukocytes; Lung; Measures; Mediating; Meningitis; Microbe; Mus; Mycoses; Myeloid Cells; Natural Immunity; Pneumococcal Infections; Pneumonia; Population; Production; Role; Sepsis; Sterility; Streptococcus pneumoniae; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Techniques; Technology; Testing; Transcript; Tumor Necrosis Factor Receptor; Vaccines; Virus Diseases; Wild Type Mouse; base; cell type; combat; cytokine; design; fascinate; genetic technology; high voltage electron microscopy; imaging modality; improved; insight; intravital imaging; invariant chain; killer T cell; knowledge of results; macrophage; member; neutrophil; novel; pathogen; receptor; research study; response

DESCRIPTION (provided by applicant): Invariant natural killer T cells (iNKT cells) are a fascinating, innate-like T lymphocyte population that recognizes glycolipids presented by CD1d, a class I-like antigen- presenting molecule. Mice deficient for iNKT cells are highly susceptible t infection by inhalation with Streptococcus pneumoniae (S. pneumoniae), a pathogen that is responsible for many deaths worldwide. We have identified glycolipid antigens from S. pneumoniae that activate the T cell antigen receptor (TCR) of iNKT cells, and we have shown TCR-dependent activation of these cells to produce IFNγ or IL-17 within hours of infection. While it is established that iNKT cells augment the innate immune response in the lung, there is little information as to how they do this, and if the separate iNKT cell subsets dedicated to IFNγ or IL-17 production behave differently. In aim one, we will use imaging and other technologies to track the iNKT cell response in the lung of infected mice. We will identify the cell types the subsets of iNKT cells interact with, their recruitment and expansion in situ, and their dynamic behavior. In aim two, we will determine how the innate immune response of myeloid cells and epithelial cells to S. pneumoniae is affected by the absence of iNKT cells, or iNKT cell production of IFNγ and/or IL-17. We have shown that the Ig super family member BTLA is important for epithelial innate responses by binding to the TNF super family receptor HVEM. Therefore, also in Aim 2, we will determine if BTLA expression by iNKT cells is required, which would be suggestive of a novel, direct interaction of iNKT cells with epithelial cells. Alternativey, a requirement for BTLA expression by another cell type, combined with data from our intravital imaging studies, would be suggestive of an indirect iNKT- epithelial cell interaction. In aim three we will identify the cell type(s) that must express CD1d for a protective response to infection using mice with a floxed Cd1d allele. Our hypothesis is that iNKT cells activate diverse elements of innate immunity in the lung, including epithelial cells, and that IFNγ and IL-17 producing iNKT cells have non redundant roles in host defense. The results from these studies will provide novel information on the innate immune response in the lung and how iNKT cells modulate this response. The increased understanding of iNKT cell function we will gain may contribute to the improved design of glycolipid adjuvants that stimulate iNKT cells to combat infections.

描述(申请人提供)：不变的自然杀伤T细胞(iNKT细胞)是一种迷人的，先天的T淋巴细胞群体，识别由CD1d提呈的糖脂，CD1d是一种I类抗原呈递分子。缺乏iNKT细胞的小鼠极易通过吸入肺炎链球菌感染，这种病原体导致全球许多人死亡。我们已经从肺炎链球菌中鉴定出能够激活iNKT细胞的T细胞抗原受体的糖脂抗原，并且我们发现这些细胞在感染后几小时内依赖于T细胞抗原受体的激活来产生干扰素γ或IL-17。虽然已经确定iNKT细胞增强肺部的先天免疫反应，但关于它们是如何做到这一点的信息很少，而且专用于产生干扰素γ或IL-17的iNKT细胞亚群是否表现不同。在第一个目标中，我们将使用成像和其他技术来跟踪感染小鼠肺内iNKT细胞的反应。我们将确定iNKT细胞亚群相互作用的细胞类型，它们在原位的招募和扩张，以及它们的动态行为。在第二个目标中，我们将确定缺乏iNKT细胞或iNKT细胞产生干扰素γ和/或IL-17如何影响髓系细胞和上皮细胞对肺炎链球菌的先天免疫反应。我们已经证明，免疫球蛋白超家族成员BTLA通过与肿瘤坏死因子超家族受体hvem结合，对上皮细胞的先天反应起重要作用。因此，同样在目标2中，我们将确定iNKT细胞是否需要表达BTLA，这将暗示iNKT细胞与上皮细胞之间新的、直接的相互作用。另一方面，另一种细胞类型对BTLA表达的要求，结合我们活体成像研究的数据，将暗示iNKT与上皮细胞的间接相互作用。在第三个目标中，我们将利用带有CD1d等位基因的小鼠识别必须表达CD1d以保护感染反应的细胞类型(S)。我们的假设是，iNKT细胞激活肺内包括上皮细胞在内的各种天然免疫元件，并且产生干扰素γ和IL-17的iNKT细胞在宿主防御中具有非多余的作用。这些研究的结果将为肺内的先天免疫反应以及iNKT细胞如何调节这种反应提供新的信息。我们将获得对iNKT细胞功能的更多了解，这可能有助于改进糖脂佐剂的设计，从而刺激iNKT细胞对抗感染。