BCL6 is required for the development of functionally responsive IgM⁺ GC Tfh–independent memory B cells

Humoral immunity depends upon long-lived, antibody-secreting plasma cells and memory B cells (MBCs). MBCs exhibit significant phenotypic and functional heterogeneity shaped by interactions with CD4⁺ T cells. It is currently unclear how specific CD4⁺ T cell interactions with B cells influence specific MBC subset generation. We used genetic ablation and antibody depletion to dissect key CD4⁺ T cell/B cell receptor–ligand pair interactions to define critical signals that govern the development of specific MBC populations. While it has previously been suggested that CD73⁺CD80⁺ MBCs are derived from the germinal center (GC), we show that highly functional CD73⁺CD80⁺ IgM⁺ MBCs differentiate in a BCL6- and CD4⁺ T cell–dependent but GC Tfh–independent manner. BCL6 upregulation, in the presence or absence of a GC, can therefore serve as a predictor of long-lived, functional MBCs.