NK cell regulation of adaptive virus immunity

体内需要 NK 细胞来杀死病毒感染的细胞。 NK 介导的病毒免疫与 先天细胞因子（例如 I 型干扰素）、持续的树突状细胞和加速获得病毒特异性 受感染动物体内的效应 T 细胞。然而，对于 NK 介导的病毒免疫的效率如何，人们知之甚少。 可以调节和塑造其他免疫细胞的成熟和/或激活概况。该提案基于 两个重组同源株中 MHC 控制下 NK 介导的病毒免疫的新遗传模型 小鼠称为 R2 和 R7。 R2 和 R7 在 MHC I 类 D 子区域仅相差约 300 kb，但是 NK 介导的病毒免疫在 R7 小鼠中非常显着。该研究项目的广泛长期目标 旨在研究 NK 介导的病毒免疫如何有效地对免疫细胞进行显着控制， 除了它们在先天免疫中的关键功能之外，还通过受控的遗传比较。一个指导 假设是 NK 介导的病毒控制 R2 和 R7 中的差异将与适应性的诱导有关 在病毒水平出现显着差异之前，通过调节细胞因子的精细平衡来实现免疫。三具体 提出目标： 目标 1. 确定 MHC 调节的 NK 细胞功能对诱导和 CD8 T 细胞对 MCMV 感染反应的动力学。来自 R2 和 R7 的 CD8 CTL 将在流程中进行评估 细胞计数和细胞毒性测定以确定诱导时间过程、反应幅度、激活状态 和感染后的效应活性。 CD8 TCR 转基因 T 细胞的过继转移将进一步定义 耐药小鼠和易感小鼠脾脏中 CDS T 细胞的诱导和效应活性。目标 2.分析NK细胞与DC相互作用对脾脏NK细胞功能的影响。脾脏的激活状态 R2和R7感染后NK细胞以及CDllc DC的频率和子集分布将是 使用流式细胞术进行分析。脾脏细胞因子的产生，尤其是 1 型干扰素和 IL-10，将 通过多重细胞因子测定进行评估。目标 3. 检查 IL-10 潜在 MHC 的潜在因果作用 NK 细胞介导的病毒免疫的调节差异。 IL-10 的潜在调节作用 将在 IL10GFP 敲入报告小鼠和 IL-10 缺陷小鼠中评估适应性免疫的诱导

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