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与外部环境存在较大的界面，并提供了抵御多种微生物的第一道防线。最初被认为是宿主和环境之间的被动屏障，现在已知肺构成了强大的免疫监视系统，其包括上皮细胞以及分布在整个传导气道和肺实质中的高度特化的专职抗原呈递细胞（APC）。然而，肺中保护性免疫的发展和免疫稳态的维持所需的关键要素在很大程度上是未知的，特别是在人体的稳态中。这一点很重要，因为肺部免疫力不受控制或失衡可能导致疾病，例如儿童期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）在启动对外源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。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发育和功能的机制。我们研究组的最新数据显示，小鼠和人类非淋巴组织中的DC网络由发育上不同且功能上专门化的DC亚群组成。在本申请中，我们建议建立肺中DC网络的功能特化，并确定在诱导粘膜抗病毒免疫中控制DC功能特化的机制。我们将通过研究小鼠体内DC，人源化小鼠模型中的人DC以及人肺来做到这一点。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网络由不同的子集组成，这些子集不同地控制对呼吸道病毒的细胞和体液免疫的诱导。拟开展的研究将通过三名已建立的研究者之间的合作进行，这些研究者具有独特且互补的专业知识，非常适合解决本申请的中心假设。本申请的主要研究者Miriam Merad博士（西奈山医学院（MSSM））是小鼠DC生物学方面的专家，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）是一位病毒学家和世界流感病毒专家。此外，Christian Becker博士（MSSM的肺病学家和Merad实验室的成员）开发了一个强大的人肺外植体计划，每年可以获得100多个新鲜的人肺样本。

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.