MHC regulation of NK cell mediated virus immunity

描述(申请人提供)：人体内需要NK细胞来抵御恶性肿瘤和病毒感染。不同个体的遗传因素会影响NK细胞识别和反应靶细胞的方式。然而，关于遗传差异如何实际影响NK细胞及其在病毒免疫中的作用，仍有许多需要了解。这一建议是基于使用PI实验室产生的几个新的MHC同源和转基因小鼠品系来模拟MHC多态对NK细胞介导的病毒免疫的影响(S)。该研究项目的长期目标是了解MHC多态如何影响NK介导的病毒免疫、其他免疫细胞以及对特定宿主的疾病保护作用。已公布的和初步的数据涉及多种机制。支持这一建议的一个指导性假设是，MHC基因多态性可以影响NK细胞显示的膜结合抑制受体，以及它们识别和应对病毒感染的能力。目的1.研究Ly49G2的表达对MHC-I型DK抵抗MCMV感染所需NK细胞的影响。我们将研究NK细胞对MCMV感染的诱导和动力学，以及这种反应对DC和病毒特异性T细胞效应细胞的影响，以确定潜在的分子和细胞病毒控制机制。目的2.探讨抑制Ly49G2受体表达对MHC-I型DK抵抗MCMV感染所需NK细胞的影响。初步数据支持Ly49G2在病毒抗性中的关键作用。将使用分子、细胞和生化策略来检测该受体及其对NK细胞的影响。目的3.探讨MHC-I DK对Ly49G2 NK细胞的许可和抑制受体信号转导的影响，以达到高效抵抗MCMV、保护脾DC和快速诱导病毒特异性CD8 T细胞免疫的目的。生化和遗传策略将被用来探测正常和抑制信号缺陷的NK细胞中的抑制性受体信号，它们获得强大的抗病毒效应活性，以及它们参与MHC-I DK依赖的病毒抵抗。相关性本建议中描述的研究的重要性和健康相关性与建立一种新的小鼠模型有关，以检查自然杀伤(NK)细胞对病毒感染的反应和控制。研究方案中特定目标的实现将促进我们对NK细胞使用的遗传、分子和细胞机制的理解，以提供对病毒感染的早期保护，并帮助激活或诱导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，该研究项目有可能解锁免疫细胞介导的治疗的新靶点，以提高疾病抵抗力，并且更好地了解天然免疫和获得性免疫之间的复杂联系可能对疫苗开发战略具有重要意义。 公共卫生相关性：这项研究计划使用PI实验室产生的几个新的MHC重组同源和转基因小鼠品系来模拟和研究MHC多态如何调节NK细胞介导的病毒免疫。目的1将阐明MHC基因多态性对NK细胞和树突状细胞在病毒耐药中的作用；目的2将研究病毒抵抗所需的NK细胞表达抑制性Ly49受体的作用；以及目的3将研究MHC基因多态性对NK细胞的效应功能教育的影响，该功能可通过NK细胞影响早期对病毒感染的抵抗力，从而影响后期的病毒特异性免疫应答。

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.