Protective lung memory B cell functions and dynamics during respiratory infection

项目摘要/摘要 人类肺部的免疫细胞暴露在各种环境微生物和过敏原中， 每一次吸气。由于肺部环境中的这些持续暴露，它们的性质和 与身体其他部位的类似免疫细胞相比，功能显然是独一无二的，但仍然很差。 明白了。我们已经成功地使用了肺炎链球菌(Sp)细菌感染小鼠模型来 表明肺常驻记忆CD4T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，防止相关但不完全相同的感染。使用这个模型，我们 最近发现，免疫球蛋白M和类转换驻留记忆B细胞也是为了响应 SP感染的方式不依赖于三级淋巴结构的诱导。尽管我们观察到 PD-L2存储器B细胞子集的存在是最大异型保护所必需的， 它们传递保护的机制尚未确定。此外，组织驻留存储器B细胞 以前只在含有三级淋巴结构的病毒感染的肺中表现出来，这 被认为对肺记忆B细胞池至关重要。尽管缺乏有组织的淋巴组织，但 SP感染模型，我们的初步数据显示，一群肺B细胞携带相关标志物 生发中心先于保护性PD-L2记忆B细胞的发育，与 CD4T细胞上PD-1和卵泡组织趋化因子CXCL13表达的一过性升高 肺部。保护性肺记忆B的建立和功能机制的研究 在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)肺常驻记忆PD-L2B细胞通过以下途径产生抗呼吸道感染的异型免疫 分泌交叉反应抗体，以及2)肺B细胞需要CD4T细胞才能产生最佳细胞 保护肺PD-L2B驻留记忆细胞。甚至在SARS-CoV-2全球卫生危机之前 从2019年末开始，下呼吸道感染一直是发病率和死亡率的主要原因 全世界。加深对保护性肺B细胞动力学及其在宿主防御中作用的理解 预防呼吸道感染将是合理设计治疗和预防策略的关键 这将刺激保护性局部B细胞的建立和活动。

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.