Early life B cell memory is archived in the mouse B-1 cell compartment and drives Chronic Lymphocytic Leukemia-like disease [bulkVDJ-seq]

The adult B cell pool is a developmental mosaic comprising short-lived naïve B cells and long-lived memory. Using genetic time-stamping, we previously showed that early life origin (ELO) B cells contributed substantially to the adult mouse immune system. In this study, we found that ELO B cells share a memory-like signature. Notably, B-1 cells exhibited an enrichment for the PD-L2/CD80 double positive (DP) immunophenotype associated with highly differentiated memory. Indeed, microbial antigen exposure in neonates expanded distinct specificities within the DP B-1 cell compartment, identifying the latter as a reservoir of IgM memory. B cell chronic lymphocytic leukemia (CLL) is a disease marked by the accumulation of memory-like B cells. By applying time-stamping to a mouse model for unmutated CLL (U-CLL), we demonstrated that leukemic expansion is driven by B-1 cell clones arising prior to postnatal day 10. Importantly, B-1 cells in mice and man closely mirrored the molecular profile of U-CLL. These results suggest that an age-associated leukemia can originate from ELO B cells.