MHC regulation of NK cell mediated virus immunity

描述（由申请人提供）：人体需要NK细胞来抵御恶性肿瘤和病毒感染。不同个体的遗传因素可以影响NK细胞对靶细胞的识别和反应。然而，关于遗传差异如何影响NK细胞及其在病毒免疫中的作用，还有很多需要了解的。该建议是基于在PI实验室产生的几种新的MHC基因和转基因小鼠株来模拟MHC多态性对NK细胞介导的病毒免疫的影响。该研究项目的长期目标是了解MHC多态性如何影响nk介导的病毒免疫、其他免疫细胞和特定宿主的疾病保护。已发表的和初步的数据暗示了多种机制。该建议的一个指导假设是MHC多态性可以影响NK细胞显示的膜结合抑制受体及其识别和响应病毒感染的能力。提出了三个具体目标：目标1。探讨Ly49G2表达对MHC-I Dk抗MCMV感染所需NK细胞的影响。NK细胞对MCMV感染的特异性反应的诱导和动力学，以及这种反应对dc和病毒特异性T细胞效应细胞的影响将被检查，以确定潜在的分子和细胞病毒控制机制。目标2。目的：探讨抑制Ly49G2受体表达对MHC-I Dk抗MCMV感染所需NK细胞的影响。初步数据支持Ly49G2在病毒抗性中起关键作用。分子，细胞和生化策略将用于检查受体及其对NK细胞的影响。目标3。评估MHC-I Dk对Ly49G2+ NK细胞许可和抑制受体信号传导的影响，以实现高效MCMV抗性、保护脾脏dc和迅速诱导病毒特异性CD8+ T细胞免疫。生化和遗传策略将用于探索正常和抑制性信号缺陷NK细胞中的抑制性受体信号，它们获得有效的抗病毒效应活性以及它们参与MHC-I Dk依赖性病毒抗性。本提案中所描述的研究的重要性和健康相关性与建立新的小鼠模型有关，以检查自然杀伤（NK）细胞对病毒感染的反应和控制。实现研究计划中的特定目标将促进我们对NK细胞用于提供早期病毒感染保护的遗传，分子和细胞机制的理解，并帮助点燃或引发最终清除复制病毒所需的病毒特异性适应性免疫反应。因此，该研究项目有可能揭示免疫细胞介导疗法的新靶点，以增强疾病抵抗力，并且对先天免疫和适应性免疫之间复杂联系的进一步了解可能对疫苗开发策略很重要。

DESCRIPTION (provided by applicant): NK cells are needed in the body to protect against malignancy and virus infection. Genetic factors in different individuals can affect how NK cells recognize and respond to target cells. However, there is still much to be learned about how genetic differences can actually influence NK cells and their role in virus immunity. This proposal is based on using several new MHC congenic and transgenic mouse strains generated in the PI's laboratory to model the effect(s) of MHC polymorphism on NK cell-mediated virus immunity. The broad long-term objective for the research project seeks to understand how MHC polymorphism imparts its effect on NK-mediated virus immunity, other immune cells and protection from disease in the given hosts. Published and preliminary data implicate multiple mechanisms. A guiding hypothesis for the proposal is that MHC polymorphism can influence membrane-bound inhibitory receptors displayed by NK cells and their capacity to recognize and respond to virus infection. Three specific aims are proposed: Aim 1. To determine the effect of Ly49G2 expression on NK cells needed in MHC-I Dk resistance to MCMV infection. The induction and kinetics of NK cells specifically responding to MCMV infection, and the effect such responses have on DCs and virus specific T cell effector cells will be examined to ascertain the underlying molecular and cellular virus control mechanisms. Aim 2. To determine the effect of inhibitory Ly49G2 receptor expression on NK cells needed in MHC-I Dk resistance to MCMV infection. Preliminary data support a critical role for Ly49G2 in virus resistance. Molecular, cellular and biochemical strategies will be used to examine the receptor and its impact on NK cells. Aim 3. To evaluate the impact of MHC-I Dk on licensing and inhibitory receptor signaling in Ly49G2+ NK cells for highly efficient MCMV resistance, protection of spleen DCs and prompt induction of virus specific CD8+ T cell immunity. Biochemical and genetic strategies will be used to probe inhibitory receptor signaling in normal and inhibitory signaling deficient NK cells, their acquisition of potent antiviral effector activity and their involvement in MHC-I Dk- dependent virus resistance. Relevance The importance and health relevance of the research described in this proposal is related to the establishment of a new mouse model to examine natural killer (NK) cells responding to and controlling virus infection. Achievement of the specific aims in the research proposal will advance our understanding of genetic, molecular and cellular mechanisms used by NK cells to provide early protection against virus infection and to help kindle or elicit virus specific adaptive immune responses needed in the eventual clearance of replicating virus. The research project therefore has the potential to unlock new targets of immune cell mediated therapy to heighten disease resistance and greater understanding of the intricate links between innate and adaptive immunity may be important for vaccine development strategies. PUBLIC HEALTH RELEVANCE: This research proposal uses several new MHC recombinant congenic and transgenic strains of mice generated in the PI's laboratory to model and investigate how MHC polymorphism can regulate NK cell- mediated virus immunity. Three aims are proposed: Aim 1 will delineate the effect of MHC polymorphism on NK and dendritic cell contributions in virus resistance; Aim 2 will examine the effect of an inhibitory Ly49 receptor expressed by NK cells needed in virus resistance; and Aim 3 will study the effect of MHC polymorphism on NK cell education of effector functions which can impact early resistance to virus infection through NK cells and consequently later virus-specific immune responses.