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）细胞增殖和稳态的体内调节。NK细胞是参与肿瘤监视的先天性淋巴细胞，在早期抗病原体宿主防御中发挥关键作用。它们在宿主对大DNA病毒如巨细胞病毒（CMV）的抗性中特别重要。事实上，具有选择性NK细胞缺陷的人患有复发性的、通常致命的疱疹病毒感染，包括CMV。NK细胞被病毒感染早期引发的细胞因子刺激，以及通过活化受体直接识别感染细胞。在C57 BL/6小鼠中，介导对鼠巨细胞病毒（MCMV）的抗性的NK细胞活化受体是Ly 49 H。Ly 49 H对其在感染细胞上的配体的识别以及随后通过其衔接分子DAP 12的信号传导刺激NK细胞产生免疫调节细胞因子并杀死感染细胞。除了这些效应子功能之外，NK细胞在病毒感染期间迅速增殖。我们已经表明，病毒诱导的增殖反应发生在三个不同的阶段，包括早期非特异性NK细胞增殖，NK细胞的优先增殖达特能够识别感染的细胞，并停止增殖与扩张的NK细胞群体的收缩。此外，我们有证据表明，aerobic和aerobic T细胞积极参与病毒诱导的NK细胞增殖的解决。虽然细胞周期进展的基本调节是很好理解的（例如，细胞分裂周期25 [Cdc 25]磷酸酶在从CDK/细胞周期蛋白复合物中去除抑制性磷酸盐中的作用），调节NK细胞增殖和体内平衡的机制仍然缺乏表征。在前一个资助期的观察基础上，我们建议研究不同Cdc 25磷酸酶在MCMV感染期间促进非特异性和优先NK细胞增殖的作用，并描述T细胞和细胞凋亡对病毒诱导的NK细胞活化和增殖的贡献。我们认为，更清楚地了解病毒感染过程中NK细胞增殖的体内调控将具有广泛的翻译意义，并可能导致新的治疗干预措施，以调节NK细胞对肿瘤和病毒的反应。

 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.