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

描述（由申请人提供）：自然杀伤细胞（NK）是先天淋巴细胞，在早期抗病原体宿主防御中起关键作用，在介导对病毒感染的抗性方面尤为重要。事实上，有选择性NK细胞缺陷的人在疱疹病毒感染时遇到了很大的困难。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它们不仅参与对细胞内病原体的初始防御，而且还影响随后的适应性免疫反应。除了杀死被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细胞优先增殖，以及增殖停止和扩大的NK细胞群收缩。参与控制NK细胞增殖的这些不同阶段的调节机制尚不清楚。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。利用小鼠巨细胞病毒（MCMV）感染作为模型系统，我们提出解决体内NK细胞增殖和稳态调节中几个关键的、尚未解决的问题，包括1)细胞因子和NK细胞激活受体对病毒诱导的NK细胞增殖的相对贡献，2)NK细胞激活受体信号增强细胞因子驱动的NK细胞增殖的机制，3)适应性免疫系统在解决病毒诱导NK细胞增殖中的作用。我们认为，对病毒感染期间体内NK细胞增殖和稳态的更清晰理解将具有广泛的翻译意义，并可能导致新的治疗干预措施来调节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）。公共卫生相关性：我们的先天免疫系统提供了对病毒感染的早期抵抗，而更特异性的适应性免疫系统正在被激活。拟议研究的总体目标是了解在病毒感染期间，我们的先天免疫反应中一种重要类型的细胞，自然杀伤细胞的调节。对病毒感染过程中自然杀伤细胞稳态的更全面了解可能会导致在病毒感染或自身免疫性疾病过程中调节自然杀伤细胞反应的新方法。

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). Public Health Relevance: Our innate immune system provides early resistance to viral infections while the more specific adaptive immune system is being activated. The overall objective of the proposed studies is to understand the regulation of one important type of cell in our innate immune response, natural killer cells, during viral infections. A more complete understanding of natural killer cell homeostasis during viral infections may lead to new ways to modulate natural killer cell responses during viral infections or autoimmune disorders.