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.

项目总结 不变自然杀伤T细胞(iNKT细胞)是一种迷人的、先天的T淋巴细胞 识别CD1d呈现的糖脂的人群，CD1d是一种I类抗原- 呈现分子。缺乏iNKT细胞的小鼠极易感染 吸入肺炎链球菌(肺炎链球菌)，这是一种 对全球许多人的死亡负有责任。我们已经鉴定出S。 肺炎杆菌激活iNKT细胞的T细胞抗原受体(TCR)，我们有 显示依赖于TCR的这些细胞在几小时内激活以产生干扰素或IL-17 感染。虽然已经确定iNKT细胞可以增强先天免疫反应 肺，关于它们是如何做到这一点的信息很少，如果分离的iNKT细胞 专用于产生干扰素或IL-17的亚群表现不同。在目标一中，我们将使用 成像和其他技术跟踪感染患者肺内iNKT细胞的反应 老鼠。我们将确定iNKT细胞的子集与其相互作用的细胞类型、其 就地招募和扩张，以及它们的动态行为。在目标二中，我们将 确定髓系细胞和上皮细胞对S。 肺炎受iNKT细胞缺失或iNKT细胞产生干扰素的影响 和/或IL-17。我们已经证明了免疫球蛋白超家族成员BTLA对 上皮细胞与肿瘤坏死因子超家族受体hvem结合的先天反应。 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细胞与上皮细胞之间的一种新的、直接的相互作用。 或者，另一种细胞类型对BTLA表达的要求与 我们的活体成像研究的数据将暗示间接的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(S) CD1d用于对感染的保护性反应，使用带有CD1d等位基因的小鼠。我们的 假说是iNKT细胞激活了肺部天然免疫的各种成分， 包括上皮细胞，而产生干扰素和IL-17的iNKT细胞没有 主机防御中的冗余角色。这些研究的结果将提供新的 肺内先天免疫反应的信息以及iNKT细胞如何对其进行调节 回应。我们对iNKT细胞功能的了解增加可能会 有助于改进糖脂佐剂的设计，刺激iNKT细胞 与感染作斗争。