Research Unit Gene Vectors, Research Group B Cell Development and Activation, Helmholtz Zentrum München, German Research Center for Environmental Health, Feodor-Lynen-Str. 21, D-81377, Munich, Germany.
TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Einsteinstraße 25, D-81675, Munich, Germany.
Nat Commun. 2024 Mar 4;15(1):1960. doi: 10.1038/s41467-024-46024-1.
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.
持续的 Notch2 信号诱导小鼠滤泡 B（FoB）细胞向边缘区 B（MZB）细胞的转分化，但这种分化途径的生理学基础仍不清楚。在这里，我们证明大多数 B 细胞接收基础 Notch 信号，该信号在 pre-MZB 和 MZB 细胞中增强。在 T 细胞依赖性免疫接种时， Notch2 的缺失或组成性激活揭示了抗原诱导的激活与 Notch2 信号之间的相互作用，其中关闭 Notch2 信号的 FoB 细胞进入生发中心（GC），而高 Notch2 信号导致 MZB 细胞的产生或浆母细胞分化的起始。Notch2 信号对于 GC 动力学不是必需的，但似乎在一些中心细胞中重新诱导，以控制 IgG1 GCB 细胞的扩增。数学模型表明，抗原激活的 FoB 细胞做出 Notch2 依赖性的二元命运决定，分化为 GCB 或 MZB 细胞。这种分支可能是一种机制，将抗原特异性克隆归档到功能和空间上不同的 B 细胞状态，以产生强大的抗体和记忆反应。
