Department of Immunology, Duke University, Durham, NC, USA.
Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA, USA.
Sci Immunol. 2022 May 6;7(71):eabn5311. doi: 10.1126/sciimmunol.abn5311.
Immunization or microbial infection can establish long-term B cell memory not only systemically but also locally. Evidence has suggested that local B cell memory contributes to early local plasmacytic responses after secondary challenge. However, it is unclear whether locality of immunization plays any role in memory B cell participation in recall germinal centers (GCs), which is essential for updating their B cell antigen receptors (BCRs). Using single B cell culture and fate mapping, we have characterized BCR repertoires in recall GCs after boost immunizations at sites local or distal to the priming. Local boosts with homologous antigen recruit the progeny of primary GC B cells to recall GCs more efficiently than do distal boosts. Recall GCs elicited by local boosts contain significantly more B cells with elevated levels of immunoglobulin (Ig) mutation and higher avidity BCRs. This local preference is unaffected by blocking CD40:CD154 interaction to terminate active, GC responses. Local boosts with heterologous antigens elicit secondary GCs with B cell populations enriched for cross-reactivity to the prime and boost antigens; in contrast, cross-reactive GC B cells are rare after distal boosts. Our results suggest that local B cell memory is retained in the form of memory B cells, GC B cells, and GC phenotype B cells that are independent of organized GC structures and that these persistent "primed B cells" contribute to recall GC responses at local sites. Our findings indicate the importance of locality in humoral immunity and inform serial vaccination strategies for evolving viruses.
免疫接种或微生物感染不仅可以在全身，还可以在局部建立长期的 B 细胞记忆。有证据表明，局部 B 细胞记忆有助于二次感染后早期的局部浆细胞反应。然而，尚不清楚免疫接种的局部性是否会影响记忆 B 细胞参与回忆生发中心（GC），这对于更新其 B 细胞抗原受体（BCR）至关重要。通过单细胞培养和谱系追踪，我们在同源抗原的局部或远距离加强免疫后，对回忆 GC 中的 BCR 库进行了特征描述。局部加强免疫比远距离加强免疫更有效地招募初级 GC B 细胞的后代进入回忆 GC。由局部加强免疫引发的回忆 GC 含有更多的 B 细胞，这些 B 细胞的免疫球蛋白（Ig）突变水平升高，BCR 亲和力更高。这种局部偏好不受阻断 CD40:CD154 相互作用以终止活跃的 GC 反应的影响。用异源抗原进行局部加强免疫会引起二次 GC，其中 B 细胞群体富含对原免疫和加强免疫抗原的交叉反应性；相比之下，在远距离加强免疫后，很少有交叉反应性 GC B 细胞。我们的结果表明，局部 B 细胞记忆以记忆 B 细胞、GC B 细胞和 GC 表型 B 细胞的形式保留下来，这些细胞独立于有组织的 GC 结构，这些持续存在的“被激活的 B 细胞”有助于局部部位的回忆 GC 反应。我们的发现表明了局部性在体液免疫中的重要性，并为不断进化的病毒的连续疫苗接种策略提供了信息。
