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

描述（由申请人提供）：呼吸上皮细胞表面与外部环境形成一个大的界面，并提供抵抗各种微生物的第一道防线。最初被认为是宿主与环境之间的被动屏障，现在已知肺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特化的专业抗原提呈细胞（APC）。然而，保护性免疫发展和维持肺部免疫稳态所需的关键因素在很大程度上是未知的，特别是在人类的稳态中。这一点很重要，因为肺部不受控制或扭曲的免疫可能导致疾病，例如，儿童时期的呼吸道合胞病毒感染与成年后易患哮喘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反应和维持对自身抗原的耐受性方面起着关键作用。Merad博士和Palucka博士的实验室十多年来一直致力于研究控制DC发展和功能的机制。我们小组最近的数据显示，小鼠和人类非淋巴组织中的DC网络由发育不同和功能特化的DC亚群组成。在这项应用中，我们建议建立肺DC网络的功能专门化，并确定控制DC功能专门化诱导粘膜抗病毒免疫的机制。我们将通过研究小鼠体内DC，人源化小鼠模型中的人类DC以及人类肺来实现这一目标。在我们的初步研究中，我们使用流感病毒来探测肺中DC亚群的功能。表达gfp的病毒与不同DC亚群的相互作用不同。我们发现不同的DC亚群优先与CD4+或CD8+ T细胞相互作用。这些结果支持了我们的假设，即肺DC网络由不同的亚群组成，这些亚群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位具有独特和互补专业知识的知名研究人员之间的合作努力来进行，这些专业知识独特地适合于解决本应用程序的中心假设。该应用程序的PI Miriam Merad博士（Mount Sinai School of Medicine， MSSM）是小鼠DC生物学方面的专家，为我们理解小鼠粘膜DC的发育和功能做出了几项关键贡献。Karolina Palucka博士（贝勒免疫学研究所（BUR）和MSSM的联合研究员）是人类DC生物学和人源化小鼠模型的世界专家。Adolfo Garcia Sastre博士（MSSM）是一名病毒学家，也是流感病毒方面的世界专家。此外，Christian Becker博士（MSSM的肺病学家，Merad实验室的成员）开发了一个强大的人体肺移植项目，每年可以获得100多个新鲜的人体肺样本。

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.