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 不变的天然杀手T细胞（INKT细胞）是一种迷人的先天淋巴细胞 识别CD1D提出的糖脂的人群，CD1D是I类样抗原 呈现分子。针对Inkt细胞的小鼠非常容易受到感染 用肺炎链球菌吸入（肺炎链球菌），一种是一种病原体 负责全球许多死亡。我们已经确定了S。 激活Inkt细胞的T细胞抗原受体（TCR）的肺炎，我们有 显示了这些细胞的TCR依赖性激活，以在数小时内产生IFN¿或IL-17 感染。虽然确定inkt细胞增强了先天性免疫反应 肺，几乎没有关于他们如何做到这一点的信息 专门针对IFN¿或IL-17生产的子集的行为不同。在目标中，我们将使用 成像和其他技术以跟踪感染肺中的Inkt细胞反应 老鼠。我们将确定inkt细胞子集与它们相互作用的细胞类型，它们 原位招聘和扩张及其动态行为。在两个目标中，我们将 确定髓样细胞和上皮细胞对S.的先天免疫反应。 肺炎受INCT细胞的缺乏或IFNCR的inkt细胞产生的影响 和/或IL-17。我们已经表明，IG超级家庭成员BTLA对 上皮的先天反应通过与TNF超级家族受体HVEM结合。 因此，同样在AIM 2中，我们将确定是否需要Inkt细胞的BTLA表达， 这将暗示inkt细胞与上皮细胞的新型直接相互作用。 另外，另一种单元格对BTLA表达的要求，并结合 来自我们的浸润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单元格类型 使用floxed CD1D等位基因的小鼠对感染的受保护反应的CD1D。我们的 假设是Inkt细胞激活了肺部先天免疫力的潜水元素， 包括上皮细胞，以及IFN¿和IL-17产生的inkt细胞没有 在主持人防御中的冗余角色。这些研究的结果将提供新颖 有关肺中先天免疫反应的信息以及Inkt细胞如何调节这一点 回复。我们将获得对Inkt细胞功能的了解增加了 有助于改进的糖脂调节器的设计，以刺激Inkt细胞到 战斗感染。