Natural Killer Cell Control of Murine Cytomegalovirus Infection

自然杀伤细胞控制鼠巨细胞病毒感染

• 批准号: 10444730
• 负责人: Wayne M. Yokoyama
• 金额: $ 66.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444730
• 关键词: Alleles; C57BL/6 Mouse; CRISPR/Cas technology; Cells; Complex; Coupled; Cytomegalovirus Infections; Data; Education; Event; Evolution; Family; Gene Cluster; Gene Family; Genes; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Human; Immune; In Vitro; Investigation; Knock-in Mouse; Laboratories; Lectin; Licensing; Ligands; Link; MHC Class I Genes; Major Histocompatibility Complex; Mediating; Memory; Mouse Strains; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Killer Cells; Normal tissue morphology; Other Genetics; Paper; Pathologic; Phenotype; Process; Publications; Publishing; Reagent; Receptor Activation; Receptor Gene; Research Personnel; Role; Serology; Signal Transduction; Surveys; Testing; Viral; Virus Diseases; base; cell killing; clinically relevant; clinically significant; epidemiology study; experimental study; genetic resistance; in vivo; insight; killer immunoglobulin-like receptor; novel; receptor; response; tool; tumor

Abstract Natural killer (NK) cells kill tumors and infected cells by integrating signals from two functional types of receptors, activation and inhibitory. In the mouse, many of these receptors belong to the Ly49 family, encoded by a cluster of highly related genes, discovered by the applicant’s laboratory. The highly polymorphic Ly49 receptors are related to killer immunoglobulin-like receptors (KIRs) on human NK cells as outstanding examples of convergent evolution. The applicant’s laboratory previously showed that the Ly49H activation receptor is responsible for genetic resistance of C57BL/6 mice to murine cytomegalovirus (MCMV) infections. Ly49H recognizes a molecule encoded by MCMV, in a manner independent of major histocompatibility complex class I (MHC-I) alleles. Studies from other groups suggest that in non-C57BL/6 mice, other Ly49 activation receptors that are not alleles of Ly49H appear to recognize MCMV-infected cells in vitro but their in vivo significance has not been established. Ironically, a recent publication from the applicant’s lab also show that Ly49 inhibitory receptors can provide NK cell-mediated protection against MCMV. This process depends on MHC-I alleles, via Ly49 inhibitory receptor-dependent licensing or education of NK cells, and their capacity to detect loss of MHC-I expression, termed missing-self, during MCMV infection. These studies provide the basis for understanding the association of human inhibitory KIRs and their MHC-I ligands that are also paradoxically associated with protection from viral infection, indicating that further studies may have clinical significance. But it has been challenging to study these receptors further in vivo due to the complexities of the Ly49 receptors, including their polymorphism and variegated expression. Here the applicant presents preliminary data in which expression of all Ly49s have been extinguished and can be replaced by a single Ly49 expressed on all NK cells. This technological advance will facilitate the further elucidation of how NK cells control MCMV infection. Thus, the Specific Aims of this proposal are to: 1) Study non-Ly49H activation receptors in NK cell responses to MCMV. 2) Characterize NK cells with inhibitory receptors mediating MCMV control. 3) Evaluate interactions between Ly49 receptors in control of MCMV. Thus, these studies will provide new insight into the mechanisms by which NK cells control viral infection.

摘要 自然杀伤（NK）细胞通过整合来自两种细胞的信号来杀死肿瘤和感染细胞。 受体的功能类型，激活型和抑制型。在老鼠体内， 属于Ly 49家族，由一组高度相关的基因编码，由 申请人的实验室高度多态的Ly 49受体与杀手相关 免疫球蛋白样受体（KIR）的人NK细胞作为突出的例子， 趋同进化申请人的实验室先前显示Ly 49 H活化 C57 BL/6小鼠对鼠巨细胞病毒的遗传抗性与受体的关系 （MCMV）感染。Ly 49 H识别MCMV编码的分子， 独立于主要组织相容性复合体I类（MHC-I）等位基因。其他研究 研究组表明，在非C57 BL/6小鼠中，其他Ly 49激活受体不是C57 BL/6小鼠的等位基因， Ly 49 H似乎在体外识别MCMV感染的细胞，但其在体内的意义还不清楚。 确立了习具有讽刺意味的是，申请人实验室最近的一份出版物也表明Ly 49 抑制性受体可以提供NK细胞介导的针对MCMV的保护。这个过程 依赖于MHC-I等位基因，通过Ly 49抑制性受体依赖性许可或NK的教育 细胞，以及它们在MCMV期间检测MHC-I表达缺失的能力，称为缺失自我， 感染这些研究为理解人类抑制性神经元与神经元之间的关系提供了基础。 KIR和它们的MHC-I配体也矛盾地与保护免受病毒感染相关， 感染，表明进一步的研究可能具有临床意义。但一直 由于Ly 49的复杂性，进一步在体内研究这些受体具有挑战性 受体，包括其多态性和多样化的表达。在此，申请人 提供了初步的数据，其中所有Ly 49的表达已经消失，可以 由在所有NK细胞上表达的单个Ly 49取代。这一技术进步将有助于 进一步阐明NK细胞如何控制MCMV感染。因此，本项目的具体目标 本研究拟：1）研究NK细胞对MCMV应答中的非Ly 49 H活化受体。（二） 用介导MCMV对照的抑制性受体表征NK细胞。3)评价 Ly 49受体在MCMV控制中的相互作用。因此，这些研究将提供新的 NK细胞控制病毒感染的机制。