Department of Immunology and Pathology, Monash University, Level 6, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3004, Australia.
Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, 305 Grattan St., Parkville, VIC 3000, Australia.
Sci Immunol. 2022 Oct 28;7(76):eabm8389. doi: 10.1126/sciimmunol.abm8389.
Vaccines work largely by generating long-lived plasma cells (LLPCs), but knowledge of how such cells are recruited is sparse. Although it is clear that LLPCs preferentially originate in germinal centers (GCs) and relocate to survival niches in bone marrow where they can persist for decades, the issues of the timing of LLPC recruitment and the basis of their retention remain uncertain. Here, using a genetic timestamping system in mice, we show that persistent PCs accrue in bone marrow at an approximately constant rate of one cell per hour over a period spanning several weeks after a single immunization with a model antigen. Affinity-based selection was evident in persisting PCs, reflecting a relative and dynamic rather than absolute affinity threshold as evidenced by the changing pattern of V gene somatic mutations conveying increased affinity for antigen. We conclude that the life span of persistent, antigen-specific PCs is in part intrinsic, preprogrammed, and varied and that their final number is related to the duration of the response in a predictable way. This implies that modulating vaccines to extend the duration of the GC reaction will enhance antibody-mediated protective immunity.
疫苗的作用主要是产生长寿浆细胞（LLPCs），但人们对这些细胞是如何被募集的知之甚少。虽然很明显，LLPCs 优先起源于生发中心（GCs），并迁移到骨髓中的存活龛位，在那里它们可以持续数十年，但 LLPC 募集的时间和它们保留的基础等问题仍然不确定。在这里，我们使用小鼠中的遗传标记系统表明，在单次用模型抗原免疫后，持续存在的 PCs 在骨髓中以大约每小时一个细胞的恒定速率积累，持续数周。在持续存在的 PCs 中可以明显看到亲和力选择，反映了相对和动态的而不是绝对的亲和力阈值，这可以通过 V 基因体细胞突变的变化模式来证明，该模式增加了对抗原的亲和力。我们得出结论，持续性、抗原特异性 PCs 的寿命部分是内在的、预先编程的，并且是多样化的，它们的最终数量与反应的持续时间以可预测的方式相关。这意味着，通过调节疫苗来延长 GC 反应的持续时间，将增强抗体介导的保护性免疫。
