NK cell Immunity to Influenza

NK细胞对流感的免疫

• 批准号: 7657174
• 负责人: PETER R PARHAM
• 金额: $ 15.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657174
• 关键词: Acute; Address; Adult; Age; Antigen-Presenting Cells; Antiviral Agents; Attenuated; Autoantigens; Autologous; Autologous Dendritic Cells; Biological; Biological Assay; CD8B1 gene; Cell Communication; Cell Surface Receptors; Cell-Mediated Cytolysis; Cells; Child; Cytolysis; Dendritic Cells; Effector Cell; Family; Flow Cytometry; Genetic Variation; Goals; Human; Immune; Immune response; Immunity; Immunogenetics; Immunoglobulins; In Vitro; Individual; Individual Differences; Infection; Influenza; Influenza A virus; Interferon Type II; Investigation; Killer Cells; Knowledge; Lead; Lymphocyte; Mediating; Memory; Methods; Modeling; Monitor; Natural Immunity; Natural Killer Cells; Nature; Other Genetics; Peptide/MHC Complex; Personal Satisfaction; Persons; Phase; Phenotype; Play; Population; Production; Purpose; Receptor Gene; Role; Severities; Stimulus; T-Lymphocyte; T-Lymphocyte Subsets; Time; Transplantation; Treatment Protocols; Tumor Tissue; Vaccinated; Vaccination; Viral Physiology; Virus; Virus Diseases; cell killing; cytokine; cytotoxicity; influenzavirus; killings; pathogen; perforin; peripheral blood; receptor; receptor expression; response

Influenza A virus is a highly successful human pathogen which naturally kills millions of people and has both potential and advantage as a biological weapon. Natural killer (NK) cells are lymphocytes of innate immunity that play a critical role in early defense against viral infections and in the initiation of the adaptive-immune response. Recent advances in knowledge of the diverse receptor phenotypes of NK cells within the individual person and of functional NK-cell interactions with dendritic cells (DC), suggest that the extensive diversity of killer cell immunoglobulin-like receptor (KIR) genes in (and between) human populations is the result of selection by viruses for NK-cell and T-cell responses that reduce the severity and time of infection. Here we propose three specific aims to study the role of NK-cells and NKcell receptors (NKR) in the human response to influenza A, with the overall goal of defining genetic and other factors that provide for superior response. Under Aim 1 the in vitro NK-cell response to influenza A will be studied using peripheral blood NK cells obtained from donors whose NK-cell immunogenetics is well defined. Both cytolysis and cytokine production will be assessed using flow cytometry, Elispot and cell-killing assays. The contributions of activating and inhibitory receptors to NK cell interaction with autologous influenza-infected DC will be defined. Aim 2 focuses on the expression of KIR and other NKR by subpopulations of memory and/or activated T cells, a general phenomenon but one which varies greatly within the human population. The expression of NKR by influenza-specific CD8 ¿ T cells from different donors will be characterised. The types and combination of NKR will be defined and analyzed for selective bias. The effects that these receptors have on the anti-viral functions of the T cells will be determined. The analysis proposed under Aim 3 will use the methods and knowledge obtained under Aim 1 to characterise the NK-cell response in subjects infected with influenza A or vaccinated against influenza A. Comparisons of the response will assess the diversity of the response, its correlation with NK-cell immunogenetics and with age. New knowledge of the nature and diversity of the human NK-cell response to influenza and of the role of NKR expression on CD8 ¿ T cells will be obtained. These results could lead to new strategies for terminating influenza infections through the manipulation or stimulation of human NK-cells and/or NKR-expressin 9 T cells.

甲型流感病毒是一种非常成功的人类病原体，它自然会导致数百万人死亡，并已 作为生物武器的潜力和优势。自然杀伤 (NK) 细胞是先天性淋巴细胞 免疫在病毒感染的早期防御和启动中发挥着关键作用 适应性免疫反应。 NK 多种受体表型知识的最新进展 个人体内的细胞以及功能性 NK 细胞与树突状细胞 (DC) 的相互作用 杀伤细胞免疫球蛋白样受体 (KIR) 基因的广泛多样性 人类群体是病毒选择 NK 细胞和 T 细胞反应的结果，这些反应减少了 感染的严重程度和时间。在这里，我们提出了研究 NK 细胞和 NK 细胞作用的三个具体目标 受体（NKR）在人类对甲型流感反应中的作用，总体目标是定义遗传和 提供卓越反应的其他因素。目标 1 体外 NK 细胞对甲型流感的反应 将使用从 NK 细胞免疫遗传学良好的供体获得的外周血 NK 细胞进行研究 定义明确。细胞溶解和细胞因子产生都将使用流式细胞术、Elispot 和 细胞杀伤试验。激活和抑制受体对 NK 细胞相互作用的贡献 将定义自体流感感染的DC。目标 2 侧重于 KIR 等的表达 NKR 由记忆和/或活化 T 细胞亚群产生，这是一种普遍现象，但 人群内部差异很大。流感特异性 CD8 ¿ T 细胞表达 NKR 来自不同捐助者的特征将被描述。 NKR的类型和组合将被定义并 分析选择性偏差。这些受体对 T 细胞抗病毒功能的影响 细胞将被确定。目标 3 下提出的分析将使用以下方法和知识 根据目标 1 获得，以表征感染甲型流感的受试者的 NK 细胞反应，或 接种甲型流感疫苗。比较反应将评估反应的多样性， 它与 NK 细胞免疫遗传学和年龄的相关性。关于自然和多样性的新知识 人类 NK 细胞对流感的反应以及 NKR 表达在 CD8 ¿ T 细胞上的作用 获得。这些结果可能会导致通过以下方式终止流感感染的新策略： 操纵或刺激人类 NK 细胞和/或表达 NKR 的 9 T 细胞。