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

描述（由申请人提供）：自然杀伤（NK）细胞是先天性淋巴细胞，在早期抗病原体宿主防御中发挥关键作用，在介导对病毒感染的抵抗力方面尤为重要。事实上，患有选择性NK细胞缺陷的人在疱疹病毒感染方面遇到了很大的困难。NK细胞杀死异常细胞并产生免疫调节细胞因子和趋化因子的能力使其独特地不仅参与对细胞内病原体的初始防御，而且影响随后的适应性免疫应答。除了杀死受感染的细胞并产生细胞因子和趋化因子外，NK细胞在病毒感染期间被刺激剧烈增殖。这种增殖反应可以分为三个不同的阶段：早期非特异性NK细胞增殖，能够识别感染细胞的NK细胞的优先增殖，以及扩增的NK细胞群体的增殖和收缩的停止。参与控制NK细胞增殖的这些不同阶段的调节机制的特征很差。这些研究的长期目标是了解病毒感染期间NK细胞增殖和稳态的体内调节。以小鼠巨细胞病毒（MCMV）感染为模型系统，我们提出了在体内NK细胞增殖和稳态调节中几个关键的、未解决的问题，包括1）细胞因子和NK细胞活化受体对病毒诱导的NK细胞增殖的相对贡献，2）NK细胞活化受体信号传导增强丝氨酸驱动的NK细胞增殖的机制，和3）适应性免疫系统在解决病毒诱导的NK细胞增殖中的作用。我们认为，更清楚地了解病毒感染期间体内NK细胞增殖和稳态将具有广泛的翻译意义，并可能导致新的治疗干预来调节NK细胞，以刺激更有效的反应（例如，在顽固性病毒感染或实体器官恶性肿瘤期间）或下调过度旺盛或不适当的反应（例如，在NK细胞淋巴增生性疾病或自身免疫性疾病期间）。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are innate lymphocytes that play a pivotal role in early anti-pathogen host defense and are particularly important in mediating resistance to viral infections. Indeed, humans with selective NK cell deficiencies experience significant difficulty with herpesviruses infections. The ability of NK cells to kill abnormal cells and produce immunomodulatory cytokines and chemokines uniquely positions them to not only participate in the initial defense against intracellular pathogens but also to influence the subsequent adaptive immune response. In addition to killing infected cells and generating cytokines and chemokines, NK cells are stimulated to vigorously proliferate during viral infections. This proliferative response can be divided into three distinct phases: early nonspecific NK cell proliferation, preferential proliferation of NK cells that are able to recognize infected cells, and cessation of proliferation and contraction of the expanded NK cell population. The regulatory mechanisms involved in controlling these different phases of NK cell proliferation are poorly characterized. The long-term objective of these studies is to understand the in vivo regulation of NK cell proliferation and homeostasis during viral infections. Using murine cytomegalovirus (MCMV) infection as a model system, we propose to address several critical, unresolved issues in the in vivo regulation of NK cell proliferation and homeostasis including 1) the relative contributions of cytokines and NK cell activation receptors to viral-induced NK cell proliferation, 2) the mechanism by which NK cell activation receptor signaling augments cytokine-driven NK cell proliferation, and 3) the role of the adaptive immune system in the resolution of viral-induced NK cell proliferation. We contend that a clearer understanding of in vivo NK cell proliferation and homeostasis during viral infections will have broad translational implications and may lead to novel therapeutic interventions to modulate NK cells to either stimulate more effective responses (e.g., during intractable viral infections or solid organ malignancies) or down-regulate over-exuberant or inappropriate responses (e.g., during NK cell lymphoproliferative disorders or autoimmune diseases).