Protective lung memory B cell functions and dynamics during respiratory infection

项目概要/摘要 人肺的免疫细胞暴露于各种环境微生物和过敏原， 每一次吸气由于在肺部环境中的这些恒定暴露，它们的性质和 与身体其他部位的类似免疫细胞相比， 明白我们已经成功地在小鼠中使用肺炎链球菌（Sp）细菌感染模型， 显示肺驻留记忆CD 4 + T细胞在局部建立并有助于异型免疫 在用异源Sp暴露引发后，针对相关但不相同的感染。利用这个模型，我们 最近发现IgM+和类别转换的常驻记忆B细胞也是响应于 以不依赖于三级淋巴样结构诱导的方式感染。尽管我们观察到 PD-L2+记忆B细胞亚群的存在是最大异型保护所必需的， 它们传达保护的机制尚未确定。此外，组织驻留记忆B细胞 以前只在含有三级淋巴样结构的病毒感染肺中得到证实， 被认为对肺记忆B细胞库至关重要。尽管缺乏有组织的淋巴组织， SP感染模型，我们的初步数据显示，一群肺B细胞携带的标志物与 在保护性PD-L2+记忆B细胞发育之前， PD-1在CD 4 + T细胞和滤泡组织趋化因子CXCL 13上的表达短暂升高， 肺阐明肺保护记忆B的建立和功能的机制 细胞缺乏异位淋巴组织的模型中，我们将继续下面描述的假设 目的：1）肺驻留记忆PD-L2+ B细胞通过以下途径赋予针对呼吸道感染的异型免疫： 交叉反应性抗体的分泌，和2）肺B细胞需要CD 4 + T细胞以进行最佳生成 保护肺PD-L2+ B驻留记忆细胞。甚至在SARS-CoV-2全球健康危机之前 从2019年底开始，下呼吸道感染已成为发病和死亡的主要原因 国际吧促进我们对保护性肺B细胞动力学和宿主防御功能的理解 对于合理设计治疗和预防策略至关重要 这将刺激保护性局部B细胞的建立和活性。

Project Summary/Abstract The immune cells of the human lung are exposed to a variety of environmental microbes and allergens with each inhalation. As a result of these constant exposures in the setting of the lung, their properties and functions compared to analogous immune cells in other parts of the body are evidently unique, but still poorly understood. We have successfully used a Streptococcus pneumoniae (Sp) bacterial infection model in mice to show that lung resident memory CD4+ T cells are established locally and contribute to heterotypic immunity against related, but non-identical infections after priming with heterologous Sp exposures. Using this model, we recently discovered that IgM+ and class-switched resident memory B cells are also established in response to Sp infections in a manner that is independent of tertiary lymphoid structure induction. Although we observed that the presence of the PD-L2+ memory B cell subset is required for maximum heterotypic protection, the mechanism by which they convey protection has not been determined. Further, tissue resident memory B cells have only been demonstrated previously in virally infected lungs containing tertiary lymphoid structures, which were thought to be crucial to the lung memory B cell pool. Despite the lack of organized lymphoid tissue in the Sp infection model, our preliminary data reveal that a population of lung B cells bearing markers associated with germinal centers precedes the development of protective PD-L2+ memory B cells, coinciding with a transient elevation in PD-1 expression on CD4+ T cells and the follicular organizational chemokine, CXCL13 in the lung. To elucidate the mechanisms underlying the establishment and function of protective lung memory B cells in a model lacking ectopic lymphoid tissues, we will pursue the hypotheses described in the following aims: 1) that lung resident memory PD-L2+ B cells confer heterotypic immunity against respiratory infection via secretion of cross-reactive antibodies, and 2) that lung B cells require CD4+ T cells for the optimal generation of protective lung PD-L2+ B resident memory cells. Even prior to the SARS-CoV-2 global health crisis beginning in late 2019, lower respiratory infections have been a leading cause of morbidity and mortality worldwide. Advancing our understanding of protective lung B cell dynamics and function in host defense against respiratory infection will be essential for the rational design of therapeutics and preventative strategies that will stimulate protective local B cell establishment and activity.