Early-life B cell memory is archived in the mouse B-1 cell compartment and drives chronic lymphocytic leukemia-like disease.

The adult B cell pool is a mosaic comprising short-lived naive B cells and long-lived memory. Using genetic time stamping, we have previously shown that early-life-origin (ELO) B cells contribute substantially to the adult mouse immune system. Here, we show that they share a memory-like signature, with ELO B-1 cells being enriched for the PD-L2/CD80 double-positive (DP) immunophenotype. Indeed, microbial antigen exposure in neonates expands distinct specificities within the DP B-1 cell compartment, identifying it as a reservoir of immunoglobulin (Ig)M memory. B cell chronic lymphocytic leukemia (CLL) is a disease marked by the accumulation of memory-like cells. By applying time stamping to a mouse model of unmutated CLL, we demonstrate that leukemic expansion is driven by B-1 clones that arise prior to postnatal day 10. Importantly, B-1 cells in mice and humans share molecular features with unmutated CLL, altogether supporting a potential contribution of ELO B cells to this disease.