Protective lung memory B cell functions and dynamics during respiratory infection

点击翻译按钮获取中文摘要

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.