This study aimed at defining the role of the B cell adaptor protein BANK1 in the appearance of age-associated B cells (ABCs) in 2 SLE mouse models (TLR7.tg6 and imiquimod-induced mice), crossed with Bank1-/- mice. The absence of Bank1 led to a significant reduction in ABC levels, also affecting other B cell populations. To gain deeper insights into their differentiation pathway and the effect of Bank1 on B cell populations, a single-cell transcriptome assay was performed. In the TLR7.tg6 model, we identified 10 clusters within B cells, including an ABC-specific cluster that was decreased in Bank1-deficient mice. In its absence, ABCs exhibited an antiinflammatory gene expression profile, while being proinflammatory in Bank1-sufficient lupus-prone mice. Trajectory analyses revealed that ABCs originated from marginal zone and memory-like B cells, ultimately acquiring transcriptional characteristics associated with atypical memory cells and long-lived plasma cells. Also, Bank1 deficiency normalized the presence of naive B cells, which were nearly absent in lupus-prone mice. Interestingly, Bank1 deficiency significantly reduced a distinct cluster containing IFN-responsive genes. These findings underscore the critical role of Bank1 in ABC development, affecting early B cell stages toward ABC differentiation, and the presence of IFN-stimulated gene-containing B cells, both populations determinant for autoimmunity.
Keywords: Adaptive immunity; Autoimmune diseases; Autoimmunity; Genetics; Mouse models.