Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization

Tea Babushku, Markus Lechner, Stefanie Ehrenberg, Ursula Rambold, Marc Schmidt-Supprian, Andrew J. Yates, Sanket Rane, Ursula Zimber-Strobl () and Lothar J. Strobl
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Tea Babushku: German Research Center for Environmental Health
Markus Lechner: German Research Center for Environmental Health
Stefanie Ehrenberg: German Research Center for Environmental Health
Ursula Rambold: German Research Center for Environmental Health
Marc Schmidt-Supprian: Technical University of Munich
Andrew J. Yates: Columbia University Irving Medical Center
Sanket Rane: Columbia University
Ursula Zimber-Strobl: German Research Center for Environmental Health
Lothar J. Strobl: German Research Center for Environmental Health

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Sustained Notch2 signals induce trans-differentiation of Follicular B (FoB) cells into Marginal Zone B (MZB) cells in mice, but the physiology underlying this differentiation pathway is still elusive. Here, we demonstrate that most B cells receive a basal Notch signal, which is intensified in pre-MZB and MZB cells. Ablation or constitutive activation of Notch2 upon T-cell-dependent immunization reveals an interplay between antigen-induced activation and Notch2 signaling, in which FoB cells that turn off Notch2 signaling enter germinal centers (GC), while high Notch2 signaling leads to generation of MZB cells or to initiation of plasmablast differentiation. Notch2 signaling is dispensable for GC dynamics but appears to be re-induced in some centrocytes to govern expansion of IgG1+ GCB cells. Mathematical modelling suggests that antigen-activated FoB cells make a Notch2 dependent binary fate-decision to differentiate into either GCB or MZB cells. This bifurcation might serve as a mechanism to archive antigen-specific clones into functionally and spatially diverse B cell states to generate robust antibody and memory responses.

Date: 2024
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DOI: 10.1038/s41467-024-46024-1

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