NATURAL KILLER CELL CONTROL OF MURINE CYTOMEGALOVIRUS INFECTION

摘要 自然杀伤(NK)细胞通过整合来自两种功能类型的信号来杀伤肿瘤和感染细胞 受体，激活和抑制。在小鼠体内，许多这些受体属于Ly49家族，编码 由申请人的实验室发现的一组高度相关的基因。高度多态的Ly49 人类NK细胞上的受体和杀伤免疫球蛋白样受体(KIRS)是融合的例子 进化论。在小鼠巨细胞病毒(MCMV)感染方面，申请人的实验室先前显示 Ly49H激活受体与C57BL/6小鼠对MCMV感染的遗传抵抗力有关。 Ly49H以独立于主要组织亲和性的方式识别MCMV编码的分子 复杂的I类(MHC-I)等位基因。然而，其他研究小组的研究表明，在非C57BL/6小鼠中，其他 Ly49激活受体等位基因识别MCMV修饰的MHC-I此外，还有其他数据表明， Ly49抑制受体也可以提供对MCMV的保护，这取决于MHC-I等位基因。一直以来 由于Ly49受体的复杂性，进一步研究这些问题具有挑战性，包括它们的 多态和错综复杂的表达。尽管如此，这些问题对于理解 人类抑制性KIR及其MHC-I配体也矛盾地与保护 病毒感染。在这里，申请人提供了MCMV由NK细胞以一种方式控制的初步数据 与Ly49H无关，但仅限于特定的MHC-I等位基因。申请者的初步数据 实验室强烈支持Ly49抑制受体的作用。因此，这项提案的具体目标是 目的：1)确定Ly49对MHC限制性MCMV的抗性；2)确定Ly49的作用 MHC限制性抗性；以及3)确定MCMV如何参与Ly49依赖的抗性。因此， 这些研究将为研究NK细胞抑制受体在感染中的作用提供新的视角。

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 and killer immunoglobulin-like receptors (KIRs) on human NK cells are examples of convergent evolution. In murine cytomegalovirus (MCMV) infection, the applicant’s laboratory previously showed that the Ly49H activation receptor is responsible for genetic resistance of C57BL/6 mice to MCMV infections. Ly49H recognizes a molecule encoded by MCMV, in a manner independent of major histocompatibility complex class I (MHC-I) alleles. However, studies from other groups suggest that in non-C57BL/6 mice, other Ly49 activation receptor alleles recognize MCMV-modified MHC-I. Moreover, still other data suggest that Ly49 inhibitory receptors can also provide protection against MCMV, depending on MHC-I alleles. It has been challenging to study these issues further due to the complexities of the Ly49 receptors, including their polymorphism and variegated expression. Nonetheless, these issues are important to understanding the role of human inhibitory KIRs and their MHC-I ligands that are also paradoxically associated with protection from viral infection. Here the applicant presents preliminary data that MCMV is controlled by NK cells in a manner independent of Ly49H but restricted to a specific MHC-I allele. Preliminary data from the applicant’s laboratory strongly support a role for a Ly49 inhibitory receptor. Thus, the Specific Aims of this proposal are to: 1) Identify Ly49 responsible for MHC-restricted resistance to MCMV; 2) Determine role of Ly49 responsible for MHC-restricted resistance; and 3) Determine how MCMV is involved in Ly49-dependent resistance. Thus, these studies will provide new insight into the function of NK cell inhibitory receptors in infection.