NK cell Immunity to Influenza

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)细胞是先天的淋巴细胞 在对病毒感染的早期防御和在启动 适应性免疫反应。NK细胞不同受体表型的研究进展 个体内的细胞以及NK细胞与树突状细胞(DC)的功能性相互作用表明 杀伤细胞免疫球蛋白样受体(KIR)基因在体内(以及之间)的广泛多样性 人类种群是病毒对NK细胞和T细胞反应的选择的结果，这种反应减少了 感染的严重程度和时间。在这里，我们提出了三个具体的目标来研究NK细胞和NK细胞的作用 人类对甲型流感的反应中的受体(NKR)，总体目标是定义遗传和 其他提供更好反应的因素。目标1下的自然杀伤细胞对甲型流感的体外反应 将使用从捐赠者的外周血NK细胞进行研究，捐赠者的NK细胞免疫遗传学是 定义得很清楚。细胞溶解和细胞因子产生将使用流式细胞术、ELISPOT和 细胞杀伤法。激活受体和抑制受体在NK细胞相互作用中的作用 将定义自体感染流感的DC。目标2侧重于KIR和其他 NKR由记忆和/或激活的T细胞亚群引起，这是一种普遍现象，但 在人类群体中有很大的差异。流感特异性CD8？T细胞表达NKR的研究 将对来自不同捐赠者的情况进行描述。将定义NKR的类型和组合，并 分析了选择性偏向。这些受体对T细胞抗病毒功能的影响 牢房将被确定。在目标3下提出的分析将使用方法和知识 在目标1下获得，以表征感染甲型流感或流感的受试者的NK细胞反应 接种甲型流感疫苗比较反应将评估反应的多样性， 其与NK细胞免疫遗传学及年龄的相关性。对自然生态系统的本质和多样性的新认识 人类NK细胞对流感的反应和CD8T细胞上NKR表达的作用将是 获得。这些结果可能导致新的战略，通过终止流感感染 操纵或刺激人类NK细胞和/或表达NKR的T细胞。

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.