Publications

Abstract

Immunological memory is characterized by the rapid re-activation of memory B cells that produce large quantities of high affinity antigen-specific Abs. This contrasts the response of naive B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naive and memory B cells is incompletely resolved. Here, we investigated the nature of BCR signaling in human splenic naive, IgM+ memory and isotype switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and SYK) and propagation (BLNK, PLCgamma2) signaling components in these different B cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared to naive cells. While no differences were observed in the magnitude of Ca2+ mobilization between subsets, IgM+ memory B cells exhibited a more rapid Ca2+ mobilization and a greater depletion of the Ca2+ ER stores, while IgG+ memory B cells had a prolonged Ca2+ uptake. Collectively, our findings show intrinsic signaling features of B-cell subsets contribute both to the robust response of human memory B cells over naive B cells. This has implications for our understanding of memory B cell responses, and provides a framework to modulate these responses in the setting of vaccination and immunopathologies such as immunodeficiency and autoimmunity.Immunology and Cell Biology accepted article preview online, 22 April 2016. doi:10.1038/icb.2016.41.