Memory B cells (MBCs) are phenotypically and functionally diverse, but their developmental origins remain undefined. Murine MBCs can be divided into subsets by expression of CD80 and PD-L2. Upon re-immunization, CD80/PD-L2 double-negative (DN) MBCs spawn germinal center B cells (GCBCs), whereas CD80/PD-L2 double-positive (DP) MBCs generate plasmablasts but not GCBCs. Using multiple approaches, including generation of an inducible GCBC-lineage reporter mouse, we demonstrate in a T cell-dependent response that DN cells formed independently of the germinal center (GC), whereas DP cells exhibited either extrafollicular (DP_EX) or GCBC (DP_GC) origins. Chromatin and transcriptional profiling revealed similarity of DN cells with an early memory precursor. Reciprocally, GCBC-derived DP cells shared distinct genomic features with GCBCs, while DP_EX cells had hybrid features. Upon restimulation, DP_EX cells were more prone to divide, while DP_GC cells differentiated toward IgG1⁺ plasmablasts. Thus, MBC functional diversity is generated through distinct developmental histories, which imprint characteristic epigenetic patterns onto their progeny, thereby programming them for divergent functional responses.

记忆 B 细胞 (MBC) 在表型和功能上具有多样性，但其发育起源仍不清楚。小鼠 MBC 可根据 CD80 和 PD-L2 的表达分为亚群。重新免疫后，CD80/PD-L2 双阴性 (DN) MBC 产生生发中心 B 细胞 (GCBC)，而 CD80/PD-L2 双阳性 (DP) MBC 产生浆母细胞，但不产生 GCBC。使用多种方法，包括生成可诱导的 GCBC 谱系报告小鼠，我们在 T 细胞依赖性反应中证明，DN 细胞独立于生发中心 (GC) 形成，而 DP 细胞表现出滤泡外 (DP _EX ) 或 GCBC ( DP _GC ) 起源。染色质和转录谱揭示了 DN 细胞与早期记忆前体的相似性。相反，GCBC 衍生的 DP 细胞与 GCBC 具有不同的基因组特征，而 DP _EX细胞则具有混合特征。再刺激后，DP _EX细胞更容易分裂，而 DP _GC细胞则分化为 IgG1 ⁺浆母细胞。因此，MBC 功能多样性是通过不同的发育历史产生的，这些发育历史将特征性的表观遗传模式烙印在其后代身上，从而对它们进行编程以产生不同的功能反应。