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: 8632820
• 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/8632820
• 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; Host Defense; Hour; Image; Immune; Immune response; In Situ; Infection; Inflammatory; Interferons; 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; public health relevance; receptor; research study; response

PROJECT SUMMARY 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 to 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 IFN¿ 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 IFN¿ 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 IFN¿ 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. Alternatively, 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 IFN¿ 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.

项目摘要 不变的自然杀伤T细胞（iNKT细胞）是一种迷人的，先天性的T淋巴细胞 识别由CD 1d（一种I类抗原）呈递的糖脂的群体- 呈递分子缺乏iNKT细胞的小鼠对感染高度敏感， 吸入肺炎链球菌（S.肺炎），一种病原体， 造成了世界范围内许多人的死亡。我们已鉴定出S. 肺炎，激活iNKT细胞的T细胞抗原受体（TCR），我们已经 显示这些细胞的TCR依赖性活化在数小时内产生IFN或IL-17， 感染虽然已经确定iNKT细胞增强了先天性免疫应答，但它可能是一种免疫抑制剂。 肺，关于它们如何做到这一点的信息很少，如果单独的iNKT细胞 专用于IFN γ或IL-17产生的亚群表现不同。在目标一中，我们将使用 成像和其他技术来跟踪感染者肺部的iNKT细胞反应， 小鼠我们将鉴定iNKT细胞亚群与之相互作用的细胞类型， 招募和扩张，以及它们的动态行为。在目标二中，我们将 确定骨髓细胞和上皮细胞对S. 肺炎是受iNKT细胞的缺乏，或iNKT细胞产生IFN？ 和/或IL-17。我们已经表明，IG超级家族成员BTLA对于 通过与TNF超家族受体HVEM结合的上皮先天性应答。 因此，同样在目标2中，我们将确定是否需要iNKT细胞表达BTLA， 这将提示iNKT细胞与上皮细胞的新的直接相互作用。 或者，需要另一种细胞类型表达BTLA，与 我们的活体成像研究数据，将提示间接的iNKT- 上皮细胞相互作用在目标三中，我们将确定必须表达的细胞类型， 使用带有floxed Cd 1d等位基因的小鼠对感染的保护性反应。我们 假设是iNKT细胞激活肺中先天免疫的多种元素， 包括上皮细胞，而产生IFN和IL-17的iNKT细胞没有 在主机防御中的冗余角色。这些研究的结果将提供新的 关于肺中先天免疫反应的信息以及iNKT细胞如何调节这一点 反应我们将获得的iNKT细胞功能的更多理解可能 有助于刺激iNKT细胞的糖脂佐剂的改进设计， 对抗感染。