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（由申请人提供）：不变的自然杀伤 T 细胞（iNKT 细胞）是一种令人着迷的、先天性 T 淋巴细胞群，可识别 CD1d（一种 I 类抗原呈递分子）呈递的糖脂。 iNKT 细胞缺陷的小鼠非常容易因吸入肺炎链球菌（S.pneumoniae）而感染，这种病原体是导致全世界许多人死亡的病原体。我们已经鉴定出来自肺炎链球菌的糖脂抗原可以激活 iNKT 细胞的 T 细胞抗原受体 (TCR)，并且我们已经证明这些细胞的 TCR 依赖性激活可在感染后数小时内产生 IFNγ 或 IL-17。虽然已确定 iNKT 细胞增强肺部的先天免疫反应，但关于它们如何做到这一点以及专用于 IFNγ 或 IL-17 产生的单独 iNKT 细胞亚群是否表现不同的信息很少。在目标一中，我们将使用成像和其他技术来追踪受感染小鼠肺部的 iNKT 细胞反应。我们将鉴定与 iNKT 细胞亚群相互作用的细胞类型、它们的原位募集和扩增以及它们的动态行为。在目标二中，我们将确定 iNKT 细胞缺失或 iNKT 细胞产生 IFNγ 和/或 IL-17 如何影响骨髓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，Ig 超家族成员 BTLA 通过与 TNF 超家族受体 HVEM 结合，对上皮先天反应非常重要。因此，同样在目标 2 中，我们将确定 iNKT 细胞是否需要 BTLA 表达，这将提示 iNKT 细胞与上皮细胞存在一种新颖的、直接的相互作用。或者，另一种细胞类型对 BTLA 表达的要求，结合我们的活体成像研究的数据，将提示 iNKT-上皮细胞之间存在间接相互作用。在目标三中，我们将使用具有 floxed Cd1d 等位基因的小鼠来鉴定必须表达 CD1d 的细胞类型，以对感染产生保护性反应。我们的假设是，iNKT 细胞激活肺部先天免疫的多种成分，包括上皮细胞，并且产生 IFNγ 和 IL-17 的 iNKT 细胞在宿主防御中具有非冗余的作用。这些研究的结果将提供有关肺部先天免疫反应以及 iNKT 细胞如何调节这种反应的新信息。我们对 iNKT 细胞功能的进一步了解可能有助于改进刺激 iNKT 细胞对抗感染的糖脂佐剂的设计。