Role of Mucosal DC Subsets in the Control of Influenza A Virus Immunity

描述(由申请人提供)：呼吸道上皮细胞表面呈现与外部环境的大界面，并提供针对广泛的微生物的第一道防线。肺最初被认为是宿主和环境之间的被动屏障，现在已知它构成了一个强大的免疫监视系统，包括上皮细胞以及分布在传导气道和肺实质中的高度专业化的专业抗原提呈细胞(APC)。然而，发展保护性免疫和维持肺内免疫动态平衡所需的关键要素在很大程度上是未知的，特别是在人类的稳定状态下。这一点很重要，因为肺部免疫不受控制或失调可能会导致疾病，例如，儿童时期的RSV感染与成年后哮喘易感性增加之间的联系可能就是这种情况。树突状细胞(DC)在启动对外来抗原的免疫应答和维持对自身抗原的耐受中起着关键作用。十多年来，梅拉德和帕卢卡博士的实验室一直致力于控制DC的发展和功能的机制。我们团队的最新数据显示，非淋巴组织中的DC网络由发育不同和功能特化的DC亚群组成，在小鼠和人类中。在这一应用中，我们建议建立肺内DC网络的功能专门化，并确定在诱导粘膜抗病毒免疫中控制DC功能专门化的机制。我们将通过在活体内研究小鼠DC、在人源化小鼠模型中研究人DC以及在人肺中研究DC来做到这一点。在我们的初步研究中，我们使用流感病毒来探索肺内DC亚群的功能。表达GFP的病毒与不同的DC亚群有不同的相互作用。我们发现不同的DC亚群优先与CD4或CD8T细胞相互作用。这些结果支持我们的假设，即肺DC网络由不同的亚群组成，它们以不同的方式控制对呼吸道病毒的细胞和体液免疫的诱导。拟议的研究将通过三名成熟的调查人员之间的合作努力进行，他们具有独特的和互补的专门知识，特别适合于解决这一申请的中心假设。该应用程序的PI Miriam Merad博士(西奈山医学院(MSSM))是小鼠DC生物学方面的专家，他为我们了解小鼠粘膜DC的发育和功能做出了几项关键贡献。Karolina Palucka博士(贝勒免疫研究所(BUR)和MSSM的联合研究员)是人类DC生物学和人源化小鼠模型方面的世界专家。Adolfo Garcia Sastre博士(MSSM)是一位病毒学家和流感病毒方面的世界专家。此外，克里斯蒂安·贝克尔博士(MSSM的肺病学家和梅拉德实验室的成员)制定了一个强大的人类肺移植计划，每年可以获得100多个新鲜的人类肺样本。

DESCRIPTION (provided by applicant): Respiratory epithelial-cell surfaces present a large interface with the external environment and provide the first line of defense against a broad array of microbes. Initially perceived as a passive barrier between the host and the environment, the lung is now known to constitute a robust system of immune surveillance that include epithelial cells as well as highly specialized professional antigen presenting cells (APC) distributed throughout the conducting airways and the lung parenchyma. However, the critical elements required for development of protective immunity and the maintenance of immune homeostasis in the lung are largely unknown, particularly in the steady state in the human. This is important because uncontrolled or skewed immunity in the lung might lead to illness as for example might be the case in the link between RSV infection in childhood and increased susceptibility to asthma in adult life. Dendritic cells (DC) play a pivotal role in initiating the immune response to foreign antigens and in the maintenance of tolerance to self antigens. Drs Merad and Palucka laboratories have been working on the mechanisms that control the development and function of DC for more than ten years. Recent data from our groups revealed that the DC networks in nonlymphoid tissues consist of developmentally distinct and functionally specialized DC subsets in mice and humans. In this application, we propose to establish the functional specialization of the DC network in the lung and identify the mechanisms that control DC functional specialization in the induction of mucosal antiviral immunity. We will do so by studying mouse DC in vivo, human DC in humanized mice models as well as human lung. In our preliminary studies we have used influenza virus to probe the function of DC subsets in the lung. GFP-expressing virus differently interacts with distinct DC subsets. We show that distinct DC subsets preferentially interact with CD4+ or CD8+ T cells. These results support our hypothesis that the lung DC network consists of different subsets that differently control the induction of cellular and humoral immunity to respiratory viruses. Research proposed will be carried out through a collaborative effort between three established investigators with distinct and complementary expertise uniquely suited to address the central hypothesis of this application. The PI of this application, Dr. Miriam Merad (Mount Sinai School of Medicine (MSSM)) is an expert in mouse DC biology and has made several key contributions to our understanding of mucosal DC development and function in mice. Dr. Karolina Palucka (Joint investigator at Baylor Institute for Immunology Research (BUR) and MSSM) is a world expert in human DC biology and in humanized mouse models. Dr. Adolfo Garcia Sastre (MSSM) is a virologist and a world expert in influenza virus. In addition, Dr. Christian Becker (a pulmonologist at MSSM and a member of Merad's laboratory) has developed a strong human lung explants program with access to more than 100 fresh human lung samples per year.