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Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation

View ORCID ProfileT. Babushku, View ORCID ProfileS. Rane, M. Lechner, View ORCID ProfileU. Zimber-Strobl, View ORCID ProfileL. J. Strobl
doi: https://doi.org/10.1101/2022.06.13.495961
T. Babushku
1Research Unit of Gene Vectors, Research Group B Cell Development and Activation, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Feodor-Lynen-Str. 21, D-81377 Munich, Germany
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S. Rane
2Irving Institute for Cancer Dynamics, Columbia University, 1190 Amsterdam Ave, New York 10027, USA
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M. Lechner
1Research Unit of Gene Vectors, Research Group B Cell Development and Activation, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Feodor-Lynen-Str. 21, D-81377 Munich, Germany
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U. Zimber-Strobl
1Research Unit of Gene Vectors, Research Group B Cell Development and Activation, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Feodor-Lynen-Str. 21, D-81377 Munich, Germany
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L. J. Strobl
1Research Unit of Gene Vectors, Research Group B Cell Development and Activation, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Feodor-Lynen-Str. 21, D-81377 Munich, Germany
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  • For correspondence: lothar.strobl@helmholtz-muenchen.de
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Abstract

Notch2 signaling has a profound role in driving the development of marginal zone B (MZB) cells. We could show recently that FoB cells act as precursors for MZB cells in mice, however, the mechanism of this differentiation is still elusive. Our current study revealed that Venus expression in CBF:H2B-Venus reporter mice, which is a proxy for Notch signaling, increases progressively with B cell maturation and is highest in MZB cells, suggesting that most peripheral B cells receive a Notch signal and cells with the highest signal preferably develop into MZB cells. Interestingly, Venus expression is heterogeneous in the MZB pool, indicating a loss of Notch signaling over time. Our data also revealed an interplay of antigen induced activation with Notch2 signals, in which FoB cells that turn off the Notch pathway enter GC reactions, whereas B cells with high Notch2 signals undergo MZB and plasmablast differentiation. While Notch2 signaling is dispensable for the initiation of the GC reaction, it supports switching to IgG1+ cells in the GC. Integration of our experimental data into a mathematical modelling framework revealed that antigen activation induces a binary cell-fate decision in FoB cells, to differentiate into either GC or MZB cells. The newly generated MZB cells have a short life span and are sustained by influx of antigen activated B cells. Our findings demonstrate that MZB cell generation is a systematic response to TD immunization and provide for the first time a detailed quantitative map of their dynamics during an ongoing TD immune response.

Competing Interest Statement

The authors have declared no competing interest.

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Posted June 21, 2022.
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Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation
T. Babushku, S. Rane, M. Lechner, U. Zimber-Strobl, L. J. Strobl
bioRxiv 2022.06.13.495961; doi: https://doi.org/10.1101/2022.06.13.495961
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Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation
T. Babushku, S. Rane, M. Lechner, U. Zimber-Strobl, L. J. Strobl
bioRxiv 2022.06.13.495961; doi: https://doi.org/10.1101/2022.06.13.495961

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