Natural Killer Cell Control of Murine Cytomegalovirus Infection

摘要 自然杀伤(NK)细胞通过整合来自两个细胞的信号来杀伤肿瘤和感染细胞 受体的功能类型，激活和抑制。在小鼠体内，许多这样的受体 属于Ly49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Ly49受体与杀手有关 人NK细胞上的免疫球蛋白样受体(KIRS)是突出的例子 趋同进化。申请人的实验室之前显示Ly49H激活 受体在C57BL/6小鼠对小鼠巨细胞病毒遗传抗性中的作用 (MCMV)感染。Ly49H识别MCMV编码的分子，在某种程度上 与主要组织相容性复合体I类(MHC-I)等位基因无关。来自其他国家的研究 研究小组认为，在非C57BL/6小鼠中，其他Ly49激活受体不是等位基因 Ly49H似乎在体外识别MCMV感染的细胞，但它们在体内的意义并不是很明显 已经建立了。具有讽刺意味的是，申请人实验室最近的一份出版物还显示，Ly49 抑制性受体可通过NK细胞提供对MCMV的保护作用。这一过程 依赖于MHC-I等位基因，通过Ly49抑制性受体依赖许可或NK教育 细胞及其在MCMV期间检测MHC-I表达丢失的能力，称为缺失自我 感染。这些研究为理解人类抑制作用的关联提供了基础。 KIRS及其MHC-I配体也矛盾地与病毒保护相关 感染，表明进一步研究可能具有临床意义。但它一直是 由于Ly49的复杂性，在体内进一步研究这些受体具有挑战性 受体，包括它们的多态和杂色表达。在这里，申请人 提供了初步数据，其中所有Ly49的表达已经消失，并且可以 取而代之的是所有NK细胞上表达的单一Ly49。这一技术进步将促进 进一步阐明NK细胞如何控制MCMV感染。因此，这一行动的具体目标是 建议：1)研究NK细胞对MCMV的非Ly49H激活受体。2) NK细胞具有介导MCMV控制的抑制性受体的特征。3)评估 Ly49受体在控制MCMV中的相互作用。因此，这些研究将提供新的 深入了解NK细胞控制病毒感染的机制。

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.