PDF(Pubmed)
Abstract：
Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control LLPC specification and survival remain poorly resolved. Using intravital two-photon imaging, we find that in contrast to most plasma cells (PCs) in the bone marrow (BM), LLPCs are uniquely sessile and organized into clusters that are dependent on APRIL, an important survival factor. Using deep, bulk RNA sequencing, and surface protein flow-based phenotyping, we find that LLPCs express a unique transcriptome and phenotype compared to bulk PCs, fine-tuning expression of key cell surface molecules, CD93, CD81, CXCR4, CD326, CD44, and CD48, important for adhesion and homing. Conditional deletion of Cxcr4 in PCs following immunization leads to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and ultimately accelerated decay of antibody titer. In naïve mice, the endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting LLPC specification is non-random. As mice age, the BM PC compartment becomes enriched in LLPCs, which may outcompete and limit entry of new PCs into the LLPC niche and pool.
摘要：
疫苗接种后的持久血清学记忆严重依赖于长寿命浆细胞(LLPC)的产生和存活。然而，控制LLPC规格和生存的因素仍然很难解决。使用活体双光子成像，我们发现，与骨髓（BM）中的大多数浆细胞（PC）相反，LLPC具有独特的固着性，并组织成依赖于APRIL的集群，一个重要的生存因素。使用深，批量RNA测序，和基于表面蛋白流的表型分析，我们发现LLPCs表达独特的转录组和表型相比，微调关键细胞表面分子的表达，CD93、CD81、CXCR4、CD326、CD44和CD48，重要表示为粘连和归巢。免疫后PC中Cxcr4的条件缺失导致BM的快速动员，降低抗原特异性PC的存活率，并最终加速抗体滴度的衰减。在幼稚的小鼠中，内源性LLPCsBCR库表现出降低的多样性，减少体细胞突变，增加了公共克隆和IgM同种型，特别是在年轻的老鼠身上，这表明LLPC规范是非随机的。随着老鼠年龄的增长，BMPC隔间富含LLPC，这可能会超过并限制新PC进入LLPC利基和池。
