B-1 cells, IgM and Protective Humoral Immunity to Influenza

甲型和B型流感病毒感染在健康人中诱导强烈的先天性和适应性免疫应答 在人类群体中，包括小鼠在内的各种动物模型都重现了这种反应。虽然 这些反应通常不会导致绝育，广泛反应性（异亚型）免疫， 从感染所有流感病毒株，他们确实大大降低死亡率和疾病的严重程度， 异亚型感染后。这种稳健响应的一个非冗余组件是生产 “天然IgM”，自发产生的抗体，广泛结合所有测试流感病毒株。 天然IgM由经典的B-1细胞和终末分化的B-1细胞在稳态下产生。 脾和骨髓中的衍生浆细胞以及流感感染后的引流淋巴液中的衍生浆细胞 通过从胸膜腔动员的CD 5 + B-1细胞的淋巴结。在它们不存在的情况下，或者在Fc- 小鼠显示，由于B细胞上的IgM受体（FcµR）， 增加肺部病毒载量，他们死于感染的速度加快。因此，天然IgM和 负责产生它们的细胞是对流感的“广泛保护”免疫的一部分， 和多样化的反应，大大减少了疾病负担和感染者的死亡。 阐明什么是最有效的，死亡率和发病率降低，广泛的免疫力， 流感对于设计新的治疗性和预防性治疗具有重要意义， 这是该提案的长期目标。因此，它响应PA-18-859，旨在支持 致力于开发通用流感病毒疫苗的研究。具体目标1是 确定B-1细胞终末分化为强IgM分泌血浆所需的信号 细胞（B-1 PC）。使用体内细胞耗竭和细胞重建实验，我们将识别信号 B-1 PC开发所需的。基因表达和功能研究将决定 和分别来自B-1 PC和B-1细胞的天然IgM的抗流感病毒活性。具体目标2将 研究TLR和BCR介导的信号对B-1细胞对流感应答的影响。我们将测试 我们假设激活CD 5 + B-1细胞的过程分为两步：TLR介导的信号诱导细胞凋亡， BCR信号传导抑制剂CD 5的增殖和丢失，使随后的BCR信号能够驱动 特异性B-1细胞应答。最后，在具体目标3中，我们将探讨非- 分泌型IgM和FcµR在增强保护性T依赖性IgG应答中的冗余功能 流感病毒在体外和体内的作用。预期成果将为理解提供概念上的进展 天然IgM、CD 5+和CD 5- B-1细胞功能，以及T依赖性B的基本过程 细胞激活这些数据将确定天然IgM作为增强广泛免疫的关键预防靶点。 对流感的体液免疫。

Influenza A and B virus infections induce robust innate and adaptive immune responses in the healthy human population, a response that is recapitulated with various animal models, including mice. Although these responses do not usually result in sterilizing, broadly reactive (heterosubtypic) immunity that protects from infection with all influenza strains, they do strongly reduce mortality rates and disease severity following heterosubtypic infections. A non-redundant component of this robust response is the production of “natural IgM”, spontaneously-produced antibodies that bind broadly to all test influenza virus strains. Natural IgM is produced in the steady-state by classical B-1 cells and by terminally-differentiated B-1- derived plasma cells in spleen and bone marrow and following influenza infection also in the draining lymph nodes by CD5+ B-1 cells mobilized from the pleural cavity. In their absence, or in the absence of the Fc- receptor for IgM (FcµR) on B cells, fully protective humoral immunity is not established, mice show increased lung viral loads, and they succumb to infection at increased rates. Thus, natural IgM and the cells responsible for their production are part of the “broadly protective” immunity to influenza, a complex and diverse response that significantly reduces disease burden and death among those infected. Elucidating what constitutes the most effective, mortality and morbidity-reducing, broad immunity to influenza is of high significance for the design of new therapeutic and prophylactic treatments, and is the long-term objective of this proposal. It is therefore responsive to PA-18-859, which aims to support research dedicated to the development of a universal influenza virus vaccine. Specific Aim 1 Is to determine the signals required for the terminal differentiation of B-1 cells to strongly IgM-secreting plasma cells (B-1PC). Using in vivo cell depletion and cell reconstitution experiments we will identify the signals required for B-1PC development. Gene expression and functional studies will determine the repertoires and anti-influenza activity of natural IgM from B-1PC and B-1 cells, respectively. Specific Aim 2 will investigate the effects of TLR and BCR-mediated signals on B-1 cell responses to influenza. We will test our hypothesis that a two-step process activates CD5+ B-1 cells: TLR-mediated signals induce cell proliferation and loss of the BCR signaling inhibitor CD5, enabling subsequent BCR-signals to drive specific B-1 cell responses. Finally, in Specific Aim 3 we will explore the mechanism underlying the non- redundant function of secreted IgM and of the FcµR in enhancing protective T-dependent IgG responses to influenza in vitro and in vivo. Expected results would provide conceptional advances for understanding natural IgM, CD5+ and CD5- B-1 cell function, and the fundamental processes underlying T-dependent B cell activation. The data would identify natural IgM as a critical prophylactic target for enhanced broad humoral immunity to influenza.