REGULATION OF VIRAL-INDUCED NK CELL PROLIFERATION DURING MURINE CMV INFECTION

 描述(由申请人提供)：我们工作的长期目标是了解病毒感染期间自然杀伤(NK)细胞增殖和体内稳态的调节。NK细胞是天然的淋巴细胞，参与肿瘤的监视，在早期的抗病原体宿主防御中发挥关键作用。它们在宿主抵抗大型DNA病毒，如巨细胞病毒(CMV)方面尤为重要。事实上，患有选择性NK细胞缺陷的人会反复感染疱疹病毒，通常是致命的，包括巨细胞病毒。NK细胞是由病毒感染早期激发的细胞因子以及通过激活受体直接识别感染细胞而刺激的。在C57BL/6小鼠中，介导对小鼠巨细胞病毒(MCMV)抗性的NK细胞激活受体为Ly49H。Ly49H识别其在感染细胞上的配体，并通过其适配分子DAP12随后发出信号，刺激NK细胞产生免疫调节细胞因子并杀死感染细胞。除了这些效应器功能外，NK细胞在病毒感染期间还会迅速增殖。我们发现病毒诱导的增殖反应发生在三个不同的阶段，包括早期的非特异性NK细胞增殖，NK细胞的优先增殖能够识别感染的细胞，以及随着扩增的NK细胞数量的收缩而停止增殖。此外，我们有证据表明，aü和d T细胞积极参与病毒诱导的NK细胞增殖的解决。尽管对细胞周期进程的基本调控已经很清楚(例如，细胞分裂周期25[CDC25]磷酸酶在从CDK/Cyclin复合体中去除抑制性磷酸盐的作用)，但调控NK细胞增殖和动态平衡的机制仍然缺乏研究。基于前一个资助时期的观察，我们建议研究不同的CDC25磷酸酶在MCMV感染期间促进非特异性和优先的NK细胞增殖中的作用，并描述T细胞和凋亡在解决病毒诱导的NK细胞激活和增殖中的作用。我们认为，更清楚地了解病毒感染期间体内对NK细胞增殖的调节将具有广泛的翻译意义，并可能导致调节NK细胞对肿瘤和病毒的反应的新的治疗干预措施。

 DESCRIPTION (provided by applicant): The long-term objective of our work is to understand the in vivo regulation of natural killer (NK) cell proliferation and homeostasis during viral infections. NK cells are innate lymphocytes that participate in tumor surveillance and play a critical role in early anti-pathogen host defense. They are particularly important in host resistance to large DNA viruses, such as cytomegalovirus (CMV). Indeed, humans with selective NK cell deficiencies suffer from recurrent, often fatal, herpesvirus infections, includin CMV. NK cells are stimulated by cytokines elicited early during viral infections, as well as by direct recognition of infected cells through activation receptors. In C57BL/6 mice, the NK cell activation receptor that mediates resistance to murine cytomegalovirus (MCMV) is Ly49H. Ly49H recognition of its ligand on infected cells and subsequent signaling through its adaptor molecule DAP12 stimulates NK cell production of immunomodulatory cytokines and killing of infected cells. In addition to these effector functions, NK cells rapidly proliferate during viral infections. We have shown that the viral-induced proliferative response occurs in three distinct phases, including early nonspecific NK cell proliferation, preferential proliferation of NK cells tat are able to recognize infected cells, and cessation of proliferation with contraction of the expanded NK cell population. Furthermore, we have evidence that aß and d T cells actively participate in the resolution of viral-induced NK cell proliferation. Although the basic regulationof progression through the cell cycle is well understood (e.g., the role of cell division cycle 25 [Cdc25] phosphatases in removing inhibitory phosphates from CDK/cyclin complexes), the mechanisms regulating NK cell proliferation and homeostasis remain poorly characterized. Building on observations made in the previous funding period, we propose to investigate the role of distinct Cdc25 phosphatases in facilitating non-specific and preferential NK cell proliferation during MCMV infection and to delineate the contributions of T cells and apoptosis to the resolution of viral-induced NK cell activation and proliferation. We contend that a clearer understanding of the in vivo regulation of NK cell proliferation during viral infections will have broad translational implications and may lead to novel therapeutic interventions to modulate NK cell responses to tumors and viruses.