Mizgerd, Joseph P.Wetzler, LeeBarker, Kimberly Alynn2021-03-082021-03-082021https://hdl.handle.net/2144/42223Streptococcus pneumoniae, or pneumococcus, remains the most prevalent cause of bacterial pneumonia worldwide. The burden of pneumococcal disease peaks among children and the elderly, while young adults are well protected against disease from all pneumococcal serotypes. Whether memory B cells play a role in this naturally developing serotype-independent immunity has not been determined. Additionally, lung resident memory B cells (BRM cells) are elicited after influenza infections of mice, but their relevance to bacterial pathogens and to humans remains unknown, as do the signals required for their establishment. We sought to address these knowledge gaps. We found that respiratory pneumococcal exposures in mice elicited lung BRM cells without concurrent tertiary lymphoid structure formation. Additionally, normal human lung tissue is enriched for B cells bearing a resident memory phenotype. Mice exposed to a low virulence pneumococcal strain were protected from a subsequent serotype-mismatched pneumococcal challenge. To address the role of B cells in this lung defense, we used a genetically engineered mouse strain allowing effective depletion of lung B cells bearing programmed death-ligand 2 (PD-L2, a memory B cell marker). When pneumococcus-experienced mice were depleted of PD-L2+ B cells just before the challenge infection, they experienced substantial defects in bacterial clearance compared to mice with lung B cells intact. These results provide the first evidence of a role for lung BRM cells in anti-bacterial immunity. Notably, this defense was pneumococcal serotype-independent, distinguishing it from the serotype-specific immunity elicited by current pneumococcal vaccines. Finally, we found that the establishment of lung BRM cells in mice requires CD4+ T cells and multiple respiratory pneumococcal exposures. A second pneumococcal infection, but not the first, induces lung chemokine (C-X-C motif) ligand 13 (CXCL13) production, establishment of local germinal center reactions, and accumulation of class-switched BRM cells in the lung. In conclusion, herein we show that lung BRM cells are a common feature of antigen-experienced lungs and describe the kinetics of lung BRM cell establishment and the role these cells play in serotype-independent lung immunity against pneumococcal pneumonia.en-USImmunologyThesis/Dissertation2021-03-03