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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

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.
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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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