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 自然杀伤（NK）细胞是先天性淋巴细胞，具有作为生物武器的潜力和优势。 免疫在病毒感染的早期防御和启动中发挥着关键作用 适应性免疫反应的最新进展。 个体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 在这里，我们提出了三个具体目标来研究 NK 细胞和 NK 细胞的作用。 受体（NKR）在人类对甲型流感的反应中的作用，总体目标是定义遗传和 目标 1 下 NK 细胞对甲型流感病毒的体外反应。 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 细胞溶解和细胞因子产生都将使用流式细胞术、Elispot 和 进行评估。 激活和抑制受体对 NK 细胞相互作用的贡献。 目标 2 将重点关注 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 流感特异性 CD8 的 NKR 表达在人群中差异很大。 T细胞 来自不同捐赠者的 NKR 类型和组合将被定义和描述。 分析这些受体对 T 抗病毒功能的影响。 目标 3 下提出的分析将使用这些方法和知识。 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 流感与甲型流感。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。 人类 NK 细胞对流感的反应以及 NKR 表达在 CD8 上的作用 ¿ T 细胞将 获得的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。