Isotype switching in human memory B cells sets intrinsic antigen-affinity thresholds that dictate antigen-driven fates

Memory B cells (MBCs) play a critical role in protection against homologous and variant pathogen challenge by either differentiating to plasma cells (PCs) or to germinal center (GCs) B cells. The human MBC compartment contains both switched IgG+ and unswitched IgM+ MBCs and at present the contribution of these MBC subpopulations to protection is incompletely understood. We discovered that intrinsic antigen-affinity thresholds for activation were at least 100-fold higher for IgG+ as compared to IgM+ MBCs and that IgG+ MBCs when challenged responded only to high affinity antigens and differentiated almost exclusively towards PC fates. In contrast, IgM+ MBCs were eliminated by apoptosis by high affinity antigens and responded to low affinity antigens by differentiating towards GC B cell fates. Thus, IgG+ and IgM+ MBCs may play distinct yet complementary roles in response to pathogen challenge to ensure the immediate production of high affinity antibodies to homologous and closely related challenges and the generation of variant-specific MBCs through GC reactions. Overall design: Comparative gene expression profiling analysis of RNA-seq data from naïve B cells (CD19+CD21+CD27-), IgM+ Memory B cells (CD19+IgM+CD21+CD27+) and IgG+ memory B cells (IgG+CD19+CD21+CD27+) from 5 healthy subjects, either unstimulated or stimulated with low- or high affintiy antigen bound to planar lipid bilayers in the presence or absence of TH media (anti-CD40+IL21+IL-4)