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

Author:

Ambegaonkar Abhijit A.1,Holla Prasida1,Sohn Haewon1ORCID,George Rachel1,Tran Tuan M.2ORCID,Pierce Susan K.1

Affiliation:

1. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852

2. Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202

Abstract

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 (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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

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