NK cell regulation of adaptive virus immunity

体内需要NK细胞来杀死感染病毒的细胞。NK介导的病毒免疫与 先天细胞因子(如I型干扰素)、持续树突状细胞和加速病毒特异性获取 感染动物体内的效应性T细胞。然而，关于NK介导的病毒免疫是如何有效的，人们知之甚少 可以调节和塑造其他免疫细胞的成熟和/或激活特征。这项建议是基于 两株重组同源毒株MHC调控下NK介导病毒免疫的新遗传模型 称为R2和R7的小鼠。R2和R7在MHC I类D亚区仅相差约300kb，但 自然杀伤细胞介导的病毒免疫在R7小鼠中表现显著。这项研究项目的长期目标是 旨在研究NK介导的病毒免疫如何有效地控制免疫细胞，在 除了它们在先天免疫中的关键功能外，通过受控的遗传比较。导游 假设在R2和R7中NK介导的病毒控制差异将与适应性诱导有关 在病毒水平明显不同之前，通过调节细胞因子的微妙平衡来免疫。三个具体的 目的：1.确定MHC调节的NK细胞功能对其诱导和释放的影响。 巨细胞病毒感染后CD8T细胞应答的动态变化来自R2和R7的CD8 CTL将在Flow中进行评估 细胞计数和细胞毒性分析确定诱导时间进程、反应幅度、激活状态 以及感染后的效应器活性。CD8 TCR转基因T细胞的过继转移将进一步定义 耐药小鼠和敏感小鼠脾CDS T细胞的诱导和效应活性。目标 2.分析NK细胞与DC相互作用对脾NK细胞功能的影响。脾的活络状态 R2和R7感染后的NK细胞和CD11c DC的频率和亚群分布 用流式细胞仪进行分析。脾细胞因子的产生，特别是1型干扰素和IL-10，将 通过多重细胞因子分析进行评估。目的3.研究IL-10在MHC中的潜在因果作用 NK细胞介导的病毒免疫的调节差异。IL-10对血管内皮细胞的潜在调节作用 将评估IL10GFP敲入报告小鼠和IL-10缺陷小鼠对适应性免疫的诱导

NK cells are needed in the body to kill virus infected cells. NK-mediated virus immunity has been linked with innate cytokines (e.g. type I interferons), sustained dendritic cells and accelerated acquisition of virus specific effector T cells in infected animals. However, little is known about how efficient NK-mediated virus immunity can regulate and shape maturation and/or activation profiles of other immune cells. This proposal is based on a new genetic model for NK-mediated virus immunity under MHC control in two recombinant congenic strains of mice referred to as R2 and R7. R2 and R7 only differ by ~300-kb in the MHC class I D subregion, but NK-mediated virus immunity is remarkable in R7 mice. The broad long-term objective for this research project seeks to examine how efficient NK-mediated virus immunity can impart dramatic control over immune cells, in addition to their critical function in innate immunity, through controlled genetic comparisons. A guiding hypothesis is that NK-mediated virus control differences in R2 and R7 will be linked with induction of adaptive immunity through regulation of a fine balance of cytokines before virus levels differ significantly. Three specific aims are proposed: Aim 1. To determine the effect of MHC regulated NK cell function on the induction and kinetics of the CD8+ T cell response to MCMV infection. CD8+ CTLs from R2 and R7 will be assessed in flow cytometric and cytotoxicity assays to ascertain the induction time course, response magnitude, activation state and effector activity after infection. Adoptive transfers with CD8+ TCR transgenic T-cells will further define the induction and the effector activity CDS T cells responding in the spleens of resistant and susceptible mice. Aim 2. To analyze the effect of NK cell-DC interactions on splenic NK cell function. Activation states for splenic NK cells and the frequency and subset distribution of CDllc+ DCs after infection of R2 and R7 will be analyzed using flow cytometry. Splenic cytokine production, especially type 1 interferon and IL-10, will be evaluated via multiplex cytokine assays. Aim 3. To examine a potential causal role for IL-10 underlying MHC regulated differences in NK cell-mediated virus immunity. A potential regulatory role for IL-10 on the induction of adaptive immunity will be evaluated in IL10GFP knock-in reporter mice and IL-10 deficient mice