MHC regulation of NK cell mediated virus immunity

MHC 调节 NK 细胞介导的病毒免疫

• 批准号: 7987843
• 负责人: Michael G Brown
• 金额: $ 38.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987843
• 关键词: Achievement; Adoptive Cell Transfers; Affect; Alleles; Antiviral Agents; Antiviral Response; Binding; Biochemical; Biochemical Genetics; Biological Models; CD8B1 gene; Cell Line; Cells; Cessation of life; Chronic; Communicable Diseases; Complex; Congenic Strain; Cytomegalovirus Infections; Cytoprotection; Data; Dendritic Cells; Disease; Disease Resistance; Education; Effector Cell; Frequencies; Genes; Genetic; Genetic Polymorphism; Goals; HIV; Health; Hepatitis C virus; Histocompatibility Antigens Class I; Human; ITGAX gene; Immune; Immune Targeting; Immune response; Immunity; Individual; KLRA1 gene; Kindling (Neurology); Kinetics; Laboratories; Learning; Licensing; Ligand Binding; Ligands; Link; Ly49G2 receptor; MHC Class I Genes; Malignant Neoplasms; Mediating; Membrane; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mouse Strains; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; PTPN6 gene; Patients; Predisposition; Publishing; Receptor Signaling; Recombinants; Regulation; Reporter; Research; Research Project Grants; Research Proposals; Resistance; Role; Signal Transduction; Spleen; T-Cell Receptor; T-Lymphocyte; Testing; Time; Transgenic Mice; Transgenic Organisms; Viral; Viral Pathogenesis; Virus; Virus Activation; Virus Diseases; adaptive immunity; base; chemokine; congenic; cytokine; cytotoxicity; interest; killings; mortality; mouse model; novel; pathogen; public health relevance; receptor; receptor expression; resistance mechanism; response; vaccine development; viral resistance

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.

描述（由申请人提供）：人体需要NK细胞来防止恶性肿瘤和病毒感染。不同个体的遗传因素会影响NK细胞对靶细胞的识别和反应。然而，关于遗传差异如何实际影响NK细胞及其在病毒免疫中的作用，还有很多东西需要了解。该提案基于使用PI实验室中生成的几种新的MHC同源和转基因小鼠品系，以模拟MHC多态性对NK细胞介导的病毒免疫的影响。该研究项目的广泛长期目标旨在了解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。公布的数据和初步数据涉及多种机制。该提案的指导假设是，MHC多态性可以影响NK细胞展示的膜结合抑制性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。确定Ly 49 G2表达对MHC-IDk抵抗MCMV感染所需的NK细胞的影响。NK细胞特异性应答MCMV感染的诱导和动力学，以及这种应答对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。目标二。确定抑制性Ly 49 G2受体表达对MHC-IDk抵抗MCMV感染所需的NK细胞的影响。初步数据支持Ly 49 G2在病毒抗性中的关键作用。分子，细胞和生物化学策略将用于检查受体及其对NK细胞的影响。目标3。评估MHC-IDk对Ly 49 G2 + NK细胞中的许可和抑制性受体信号传导的影响，以用于高效MCMV抗性、脾DC的保护和病毒特异性CD 8 + T细胞免疫的迅速诱导。生物化学和遗传策略将用于探测正常和抑制性信号传导缺陷型NK细胞中的抑制性受体信号传导、它们获得有效的抗病毒效应子活性以及它们参与MHC-I Dk依赖性病毒抗性。相关性本提案中所述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。研究提案中具体目标的实现将促进我们对NK细胞所使用的遗传，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，该研究项目有可能解锁免疫细胞介导治疗的新靶点，以提高疾病抵抗力，并且更好地了解先天免疫和适应性免疫之间的复杂联系可能对疫苗开发策略很重要。 公共卫生相关性：本研究计划使用PI实验室中产生的几种新的MHC重组同源和转基因小鼠品系来建模和研究MHC多态性如何调节NK细胞介导的病毒免疫。提出了三个目标：目的1将阐明MHC多态性对NK细胞和树突状细胞在病毒抵抗中的作用，目的2将检测NK细胞表达的抑制性Ly 49受体在病毒抵抗中的作用;目的3将研究MHC多态性对NK细胞效应功能教育的影响，这些效应功能可以通过NK细胞影响对病毒感染的早期抵抗力，从而影响后期的病毒感染。特异性免疫反应。