Anti-viral DC/NK interactions

描述（由申请方提供）：人类在其次级淋巴器官中存在大量自然杀伤（NK）细胞。这些NK细胞富含免疫调节性CD 56 brightCD 16-细胞，其优先被树突状细胞（DC）激活。我们的初步数据表明，NK细胞激活的DC限制B细胞转化的爱泼斯坦巴尔病毒（EBV）在体外，特别是当NK细胞来自扁桃体，初级EBV感染的次级淋巴器官。EBV是一种人类肿瘤病毒，其在超过90%的人类成年人群中建立潜伏感染。在免疫功能正常的个体中，它引起上皮和B细胞来源的肿瘤，并且在免疫功能低下的个体中频率增加。对EBV的先天免疫的表征特别令人感兴趣，因为这种初始免疫控制的失败可能导致在初次免疫应答期间病毒滴度增加和大量T细胞扩增，从而导致传染性单核细胞增多症。为了表征EBV感染期间DC/NK细胞相互作用的作用，我们计划：1.表征EBV感染期间的先天NK细胞活化。我们将剖析DC/NK细胞突触形成、由EBV衍生的dsRNA激活的DC以及用于其由EBV激活的扁桃体DC亚群。2.分析扁桃体NK细胞的保护效应功能。我们将集中在细胞因子的产生，细胞毒性和援助后，通过EB病毒感染的DC激活NK细胞的保护性T细胞极化。3.研究体内EBV感染。为了将我们的体外发现转化为原发性EBV感染的体内模型，我们在免疫受损小鼠中重建了人免疫系统，这可以建立针对EBV的原发性保护性免疫应答。将探索该模型以研究原发性EBV感染期间NK细胞的扩增和活化、NK细胞对EBV的先天免疫控制的贡献以及它们在EBV的适应性免疫控制的T细胞极化中的协助。这些研究将在体外和体内表征DC激活NK细胞的机制，以及NK细胞对致癌EBV转化B细胞的保护功能。建立保护性EBV特异性免疫控制的知识可能建议针对常见EBV相关肿瘤如鼻咽癌和霍奇金淋巴瘤的疫苗接种策略。 公共卫生相关性：爱泼斯坦巴尔病毒（EBV）在人群中引起上皮和B细胞来源的肿瘤，如霍奇金淋巴瘤和鼻咽癌。该提案计划研究先天免疫系统的两种细胞类型，树突状细胞和自然杀伤细胞，如何相互作用以最初控制EBV并影响其他免疫细胞，以建立终身保护，免受EBV相关恶性肿瘤的发展。在建立EBV特异性免疫控制过程中对这些初始事件的理解将有助于我们解释为什么一些个体会发生EBV的症状性急性感染，称为传染性单核细胞增多症，并确定应利用的免疫区室，以有效地接种EBV相关肿瘤。

DESCRIPTION (provided by applicant): Humans harbor a substantial Natural Killer (NK) cell compartment in their secondary lymphoid organs. These NK cells are enriched for immunoregulatory CD56brightCD16- cells, which are preferentially activated by dendritic cells (DCs). Our preliminary data demonstrate that NK cell activation by DCs restricts B cell transformation by the Epstein Barr virus (EBV) in vitro, especially when the NK cells are derived from tonsils, the secondary lymphoid organ of primary EBV infection. EBV is a human tumorvirus, which establishes latent infection in more than 90% of the human adult population. It causes tumors of epithelial and B cell origin in immune competent, and at increased frequencies in immune compromised individuals. The characterization of innate immunity to EBV is of particular interest, because failure of this initial immune control might result in increased viral titers and massive T cell expansion during primary immune responses, resulting in infectious mononucleosis. In order to characterize the role of DC/NK cell interactions during EBV infections, we plan to: 1. Characterize innate NK cell activation during EBV infection. We will dissect DC/NK cell synapse formation, DC activation by EBV derived dsRNA, and tonsillar DC subsets for their activation by EBV. 2. Analyze the protective effector functions of tonsillar NK cells. We will focus on cytokine production, cytotoxicity and assistance in protective T cell polarization by NK cells after DC activation via EBV infection. 3. Investigate EBV infection in vivo. In order to translate our in vitro findings into an in vivo model of primary EBV infection, we have reconstituted human immune systems in immune compromised mice, which could mount primary protective immune responses against EBV. This model will be explored to investigate NK cell expansion and activation during primary EBV infection, the contribution of NK cells to innate immune control of EBV, and their assistance in T cell polarization of adaptive immune control of EBV. These studies will characterize the mechanisms of NK cell activation by DCs, and protective NK cell functions against B cell transformation by oncogenic EBV in vitro and in vivo. Knowledge of the establishment of protective EBV specific immune control might suggest vaccination strategies against common EBV associated tumors like nasopharyngeal carcinoma and Hodgkin's lymphoma. PUBLIC HEALTH RELEVANCE: Epstein Barr virus (EBV) causes tumors of epithelial and B cell origin in the human population, like Hodgkin's lymphoma and nasopharyngeal carcinoma. This proposal plans to investigate how two cell types of the innate immune system, dendritic cells and Natural Killer cells, interact to initially control EBV and influence other immune cells to establish life-long protection from the development of EBV associated malignancies. An understanding of these initial events during the establishment of EBV specific immune control will help us explain why some individuals develop symptomatic acute infection with EBV, called infectious mononucleosis, and identify immune compartments that should be harnessed to efficiently vaccinate against EBV associated tumors.