Central and Effector B cells in the Lung

描述（由申请人提供）：B细胞记忆——定义为长期维持抗原特异性B细胞和浆细胞——对大多数当前疫苗（包括流感疫苗）的成功至关重要。然而，我们对这些细胞如何以及在哪里产生和维持的理解是不完整的。因此，很难合理设计新的疫苗来有效地诱导B细胞记忆或干预记忆B细胞导致疾病的情况。尽管记忆B细胞已经在人类中被发现，但直到最近，它们在小鼠中的对应体还很难被发现。因此，虽然我们对记忆B细胞的样子有了一些了解，特别是在人体血液中，但我们对组织中维持的记忆B细胞知之甚少。例如，记忆B细胞似乎存在于先前感染过流感的小鼠（想必也包括人类）的肺部。然而，我们不知道这些记忆细胞与在血液中循环的记忆细胞有何不同。该提案将定义中枢记忆B细胞（在次要淋巴器官）和外周非淋巴器官（如肺）的效应记忆B细胞的特征。我们还将确定维持肺中记忆B细胞和浆细胞的机制，确定记忆B细胞募集（或生成）到肺的时间，确定肺中记忆B细胞与其他部位相比的特异性和寿命，并测试支气管相关淋巴组织（BALT）的存在是否会改变肺中记忆B细胞的组成、寿命或活性。总之，这些实验将确定表型，更重要的是，在外周组织中维持的效应记忆B细胞的功能。因此，这些结果将为合理设计保护呼吸道的疫苗提供信息，并导致增强或减少肺中记忆B细胞的产生和维持的治疗方法。

DESCRIPTION (provided by applicant): B cell memory - defined as antigen-specific B cells and plasma cells that are maintained over the long-term - is essential for the success of most current vaccines, including those to influenza. However, our understanding of how and where these cells are generated and maintained is incomplete. Thus, it is difficult to rationally design new vaccines that will efficiently elicit B cell memory or to intervene in situations in which memory B cells contribute to disease. Although memory B cells have been phenotypically identified in humans, their counterparts in mice have been, until recently, more difficult to identify. Thus, while we have some idea of what memory B cells look like, particularly in human blood, we have much less understanding of the memory B cells that are maintained in tissues. For example, memory B cells appear to be maintained in the lungs of mice (and presumably humans) that have been previously infected with influenza. However, we have no idea how these memory cells differ from their counterparts that circulate in the blood. This proposal will define the characteristics of central memory B cells (in secondary lymphoid organs) and effector memory B cells in peripheral non-lymphoid organs, such as the lung. We will also determine the mechanisms that maintain memory B cells and plasma cells in the lung, define the timing of memory B cell recruitment (or generation) to the lung, determine the specificities and longevity of the memory B cells in the lung compared to other sites and test whether the presence of Bronchus Associated Lymphoid Tissue (BALT) alters the composition, lifespan or activity of memory B cells in the lung. Together, these experiments will determine the phenotype and more importantly, the function of effector memory B cells that are maintained in peripheral tissues. Thus, these results will inform the rational design of vaccines that protect the respiratory tract and lead to therapies that enhance or curtail the generation and maintenance of memory B cells in the lung. PUBLIC HEALTH RELEVANCE: The experiments in this project will facilitate the identification and characterization of central and effector memory B cells that reside in lymphoid organs or peripheral non-lymphoid tissues. Given that successful vaccination against influenza is dependent on the generation of long-lived memory B cells and plasma cells, these experiments will help us to develop more effective vaccines against influenza and other infectious diseases.