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死肿瘤和感染细胞。 受体，激活和抑制。在小鼠中，许多这些受体属于Ly 49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Ly 49 人NK细胞上的杀伤免疫球蛋白样受体（KIR）是会聚性免疫球蛋白样受体的实例。 进化在鼠巨细胞病毒（MCMV）感染中，申请人的实验室先前显示， Ly 49 H活化受体负责C57 BL/6小鼠对MCMV感染的遗传抗性。 Ly 49 H识别MCMV编码的分子，其识别方式与主要组织相容性无关 复合I类（MHC-I）等位基因。然而，来自其他组的研究表明，在非C57 BL/6小鼠中，其他 Ly 49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， Ly 49抑制性受体也可以提供针对MCMV的保护，这取决于MHC-I等位基因。已经 由于Ly 49受体的复杂性，进一步研究这些问题具有挑战性， 多态性和多样化表达。尽管如此，这些问题对于理解 人抑制性KIR和它们的MHC-I配体也矛盾地与 病毒感染在此，申请人提供了MCMV由NK细胞控制的初步数据， 独立于Ly 49 H，但限于特定的MHC-I等位基因。申请人的初步数据 实验室强烈支持Ly 49抑制性受体作用。因此，本提案的具体目标是 目的：1）鉴定负责MHC限制性MCMV抗性的Ly 49; 2）确定负责MHC限制性MCMV抗性的Ly 49的作用 用于MHC限制性抗性;和3）确定MCMV如何参与Ly 49依赖性抗性。因此，在本发明中， 这些研究将对NK细胞抑制性受体在感染中的功能提供新的认识。

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.