In Vitro Generation of Long-lived Human Plasma Cells
In Vitro Generation of Long-lived Human Plasma Cells
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DOI：
10.4049/jimmunol.1103720
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发表时间：
2012-12-15
影响因子：
4.4
通讯作者：
Tooze, Reuben M.
中科院分区：
文献类型：
--
作者：
Cocco, Mario;Stephenson, Sophie;Tooze, Reuben M.
浆细胞（PC），体液免疫的终端效应器，是短暂的，除非支持的生态位环境中，他们可能会持续多年。没有模型系统已经将B细胞活化与小生境功能联系起来，以允许体外产生长寿命的PC。因此，B细胞终末分化的完整轨迹还有待于在体外研究。在这篇文章中，我们描述了一个强大的模型，从外周血B细胞的多克隆长寿的人PC的生成。在浆母细胞增殖阶段之后，PC在没有细胞分裂的情况下持续存在，其活力仅受到选择性培养终止的限制。PC寿命的保守预测是300天，但有可能显着延长一些细胞的寿命。这些长寿命的PC优先来源于记忆B细胞，并获得类似于人骨髓PC的CD 138（高）表型。对整个系统中基因表达的分析定义了具有相关动力学和相关功能特征的基因簇。重要的是，这些分化簇中的基因表现出体外和离体PC相似的总体表达模式。体外PC完全重编程为分泌状态，并适应其分泌负荷，在不存在XBP 1 mRNA剪接的情况下维持120 pg/细胞/天的IgG分泌。据我们所知，通过建立一组足以使成熟的人PC在体外的发展和持久性的条件，我们提供了第一个平台，依次探索和操纵人PC分化的每个阶段。免疫学杂志，2012，189：5773-5785。
Plasma cells (PCs), the terminal effectors of humoral immunity, are short-lived unless supported by niche environments in which they may persist for years. No model system has linked B cell activation with niche function to allow the in vitro generation of long-lived PCs. Thus, the full trajectory of B cell terminal differentiation has yet to be investigated in vitro. In this article, we describe a robust model for the generation of polyclonal long-lived human PCs from peripheral blood B cells. After a proliferative plasmablast phase, PCs persist in the absence of cell division, with viability limited only by elective culture termination. Conservative predictions for PC life expectancy are 300 d, but with the potential for significantly longer life spans for some cells. These long-lived PCs are preferentially derived from memory B cells, and acquire a CD138(high) phenotype analogous to that of human bone marrow PCs. Analysis of gene expression across the system defines clusters of genes with related dynamics and linked functional characteristics. Importantly, genes in these differentiation clusters demonstrate a similar overall pattern of expression for in vitro and ex vivo PCs. In vitro PCs are fully reprogrammed to a secretory state and are adapted to their secretory load, maintaining IgG secretion of 120 pg/cell/day in the absence of XBP1 mRNA splicing. By establishing a set of conditions sufficient to allow the development and persistence of mature human PCs in vitro, to our knowledge, we provide the first platform with which to sequentially explore and manipulate each stage of human PC differentiation. The Journal of Immunology, 2012, 189: 5773-5785.