Clonally expanded IgG, but not IgA, antibody-secreting cells preferentially target influenza nucleoprotein following homologous and heterologous infections.

Infection with influenza virus remains a significant global health concern due to its ability to acquire mutations at key antigenic sites to escape antibody recognition. While germinal center (GC) and memory B cells have been well studied following influenza infection, the clonal dynamics of antibody secreting cells (ASCs), particularly those within the bone marrow (BM) niche that are responsible for serum immune protection, remain poorly understood. Here, we combine single-cell RNA (scRNA) and B cell receptor (BCR) sequencing to characterize individual ASCs following various Influenza exposure histories. We find that BM repertories are populated by highly expanded and class-switched ASCs following Influenza infection with similar transcriptional and repertoire characteristics regardless of homologous or heterologous infection histories. By combining single-cell analysis with monoclonal antibody expression and characterization, we find that a large proportion of the expanded IgG-, but not IgA-, ASC repertoire demonstrates specificity to influenza nucleoprotein (NP). Together, our data reveal the complex relationship between BM ASC repertoires, mucosal humoral immune responses, and BCR antigen specificity during influenza infection.