BCL6 is required for the development of functionally responsive IgM+ GC-independent Memory B Cells

Abstract

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 the critical signals that govern the development of specific MBC populations. While it has previously been suggested that germinal center (GC) experience is required for the development of CD73+CD80+ MBCs that rapidly form secondary plasmablasts, highly functional IgM+ MBCs differentiate in a BCL6 and CD4+ T cell-dependent, but GC-independent manner. BCL6 upregulation, in the presence or absence of a GC, can therefore serve as a predictor of long-lived, functional MBCs. One Sentence SummaryDifferential requirements of BCL6 and Tfh cells lead to the generation of functionally distinct memory B cell populations.