Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions
Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions
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DOI：
10.1073/pnas.1416276112
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发表时间：
2015-02-10
影响因子：
11.1
通讯作者：
Kueppers, Ralf
中科院分区：
文献类型：
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作者：
Seifert, Marc;Przekopowitz, Martina;Kueppers, Ralf
IgV基因突变的人外周血（PB） IgM(+) IgD(+)CD27(+) B淋巴细胞的产生和功能一直存在争议。我们测定了它们在初始B细胞和IgM-only和IgG（+）记忆B细胞中的差异基因表达。该分析揭示了IgM(+)(IgD(+))CD27（+）和IgG（+）记忆B细胞的高度相似性，但也指出了这两个亚群的不同功能能力。体外分析显示，活化的IgM(+)IgD(+)CD27(+) B细胞倾向于迁移到B细胞卵泡并经历生发中心（GC） B细胞分化，而活化的IgG（+）记忆B细胞优先表现为浆细胞（PC）命运。b细胞淋巴瘤6和PR结构域1以及BTB和CNC同源物1、亮氨酸拉链转录因子2表达的反向调控支持了这一观察结果。此外，IgM(+)IgD(+)CD27(+) B淋巴细胞优先响应中性粒细胞来源的细胞因子。儿茶酚胺、癌胚抗原细胞粘附分子8 （CEACAM8）和ifn - γ的共刺激可引起IgM（+）、IgD（+）、CD27(+) B细胞向PCs分化，诱导类别转换为IgG2，并且在与中性粒细胞共培养中可重复。总之，本研究证实了人IgM(+)IgD(+)CD27(+) B细胞的记忆B细胞特征，它们与IgG(+) gc后B细胞具有典型的记忆B细胞转录模式，并表现出更快、更有力的再刺激潜力，这是免疫记忆的标志。此外，这项工作揭示了人类IgM记忆B细胞的功能可塑性，通过显示它们在再激活时发生继发性GC反应的倾向，以及它们通过与免疫调节中性粒细胞相互作用在早期炎症中的特殊作用。
The generation and functions of human peripheral blood (PB) IgM(+) IgD(+)CD27(+) B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG(+) memory B cells. This analysis revealed a high similarity of IgM(+)(IgD(+))CD27(+) and IgG(+) memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM(+)IgD(+)CD27(+) B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG(+) memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM(+)IgD(+)CD27(+) B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-gamma caused differentiation of IgM(+)IgD(+)CD27(+) B cells into PCs, induced class switching to IgG2, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM(+)IgD(+)CD27(+) B cells in that they share typical memory B-cell transcription patterns with IgG(+) post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils.