Ambegaonkar, Abhijit A.Holla, PrasidaSohn, HaewonGeorge, RachelTran, Tuan M.Pierce, Susan K.2024-10-282024-10-282024Ambegaonkar AA, Holla P, Sohn H, George R, Tran TM, Pierce SK. Isotype switching in human memory B cells sets intrinsic antigen-affinity thresholds that dictate antigen-driven fates. Proc Natl Acad Sci U S A. 2024;121(13):e2313672121. doi:10.1073/pnas.2313672121https://hdl.handle.net/1805/44273Memory 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 (GC) B cells. The human MBC compartment contains both switched IgG+ and unswitched IgM+ MBCs; however, whether these MBC subpopulations are equivalent in their response to B cell receptor cross-linking and their resulting fates is incompletely understood. Here, we show that IgG+ and IgM+ MBCs can be distinguished based on their response to κ-specific monoclonal antibodies of differing affinities. IgG+ MBCs responded only to high-affinity anti-κ and differentiated almost exclusively toward PC fates. In contrast, IgM+ MBCs were eliminated by apoptosis by high-affinity anti-κ but responded to low-affinity anti-κ by differentiating toward GC B cell fates. These results suggest that IgG+ and IgM+ MBCs may play distinct yet complementary roles in response to pathogen challenge ensuring the immediate production of high-affinity antibodies to homologous and closely related challenges and the generation of variant-specific MBCs through GC reactions.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalMemory B cellsAffinity thresholdsB cell receptor isotypeArticle