Deep profiling of antigen-specific B cells from different pathogens identifies novel compartments in the IgG memory B cell and antibody-secreting cell lineages

Claireaux, M.; Elias, G.; Kerster, G.; Kuijper, L. H.; Duurland, M. C.; Paul, A. G.; Burger, J. A.; Poniman, M.; Olijhoek, W.; de Jong, N.; de Jongh, R.; Wynberg, E.; van Willigen, H. D.; Prins, M.; de Bree, G. J.; de Jong, M. D.; Kuijpers, T. W.; Eftimov, F.; van der Schoot, C. E.; Rispens, T.; Garcia-Vallejo, J. J.; ten Brinke, A.; van Gils, M. J.; van Ham, S. M.

doi:10.1101/2023.12.19.572339

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bioRxiv · 10.1101/2023.12.19.572339

Deep profiling of antigen-specific B cells from different pathogens identifies novel compartments in the IgG memory B cell and antibody-secreting cell lineages

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Abstract

A better understanding of the bifurcation of human B cell differentiation into memory B cells (MBC) and antibody-secreting cells (ASC) and identification of MBC and ASC precursors is crucial to optimize vaccination strategies or block undesired antibody responses. To unravel the dynamics of antigen-induced B cell responses, we compared circulating B cells reactive to SARS-CoV-2 (Spike, RBD and Nucleocapsid) in COVID-19 convalescent individuals to B cells specific to Influenza-HA, RSV-F and TT, induced much longer ago. High-dimensional spectral flow cytometry indicated that the decision point between ASC- and MBC-formation lies in the CD43+CD71+IgG+ Activated B cell compartment, showing properties indicative of recent germinal center activity and recent antigen encounter. Within this Activated B cells compartment, CD86+ B cells exhibited close phenotypical similarity with ASC, while CD86- B cells were closely related to IgG+ MBCs. Additionally, different activation stages of the IgG+ MBC compartment could be further elucidated. The expression of CD73 and CD24, regulators of survival and cellular metabolic quiescence, discerned activated MBCs from resting MBCs. Activated MBCs (CD73-CD24lo) exhibited phenotypical similarities with CD86- IgG+ Activated B cells and were restricted to SARS-CoV-2 specificities, contrasting with the resting MBC compartment (CD73-/CD24hi) that exclusively encompassed antigen-specific B cells established long ago. Overall, these findings identify novel stages for IgG+ MBC and ASC formation and bring us closer in defining the decision point for MBC or ASC differentiation. ImportanceIn this study, researchers aimed to better understand human B cell differentiation and their role in establishing long-lived humoral immunity. Using high-dimensional flow cytometry, they studied B cells reactive to three SARS-CoV-2 antigens in individuals convalescent for COVID-19, and compared their phenotypes to B cells reactive to three distinct protein antigens derived from vaccines or viruses encountered months to decades before. Their findings showed that Activated B cells reflect recent germinal center graduates that may have diverse fates; with some feeding the pool of antibody-secreting cells and others fueling the resting memory B cell compartment. Activated B cells gradually differentiate into resting memory B cells through an activated MBC phase. Increased expression of the cellular metabolic regulators CD73 and CD24 in resting memory B cells distinguishes them from the activated memory B cells phase, and is likely involved in sustaining a durable memory of humoral immunity. These findings are crucial for the development of vaccines that provide lifelong protection and may show potential to define reactive B cells in diseases where the cognate-antigen is still unknown such as in autoimmunity, cancers, or novel viral outbreaks.

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Claireaux, M., Elias, G., Kerster, G., Kuijper, L. H., Duurland, M. C., Paul, A. G., Burger, J. A., Poniman, M., Olijhoek, W., de Jong, N., de Jongh, R., Wynberg, E., van Willigen, H. D., Prins, M., de Bree, G. J., de Jong, M. D., Kuijpers, T. W., Eftimov, F., van der Schoot, C. E., Rispens, T., Garcia-Vallejo, J. J., ten Brinke, A., van Gils, M. J., van Ham, S. M.. 2023-12-20. Deep profiling of antigen-specific B cells from different pathogens identifies novel compartments in the IgG memory B cell and antibody-secreting cell lineages. https://doi.org/10.1101/2023.12.19.572339

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