Seifert Marc, Przekopowitz Martina, Taudien Sarah, Lollies Anna, Ronge Viola, Drees Britta, Lindemann Monika, Hillen Uwe, Engler Harald, Singer Bernhard B, Küppers Ralf
Institute of Cell Biology (Cancer Research).
Institute for Transfusion Medicine.
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):E546-55. doi: 10.1073/pnas.1416276112. Epub 2015 Jan 26.
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-γ 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.
人类外周血（PB）中具有体细胞突变IgV基因的IgM(+)IgD(+)CD27(+) B淋巴细胞的产生及其功能存在争议。我们确定了它们与初始B细胞、仅表达IgM的B细胞以及IgG(+)记忆B细胞的差异基因表达。该分析揭示了IgM(+)(IgD(+))CD27(+)和IgG(+)记忆B细胞具有高度相似性，但也指出了这两个亚群不同的功能能力。体外分析显示，活化的IgM(+)IgD(+)CD27(+) B细胞有迁移至B细胞滤泡并经历生发中心（GC）B细胞分化的倾向，而活化的IgG(+)记忆B细胞则优先表现出向浆细胞（PC）分化的命运。B细胞淋巴瘤6和含PR结构域蛋白1以及差异BTB和CNC同源蛋白1、碱性亮氨酸拉链转录因子2表达的反向调节支持了这一观察结果。此外，IgM(+)IgD(+)CD27(+) B淋巴细胞优先对中性粒细胞衍生的细胞因子作出反应。儿茶酚胺、癌胚抗原细胞黏附分子8（CEACAM8）和IFN-γ的共刺激导致IgM(+)IgD(+)CD27(+) B细胞分化为PC，诱导类别转换为IgG2，并且在与中性粒细胞共培养时可重复。总之，本研究证实了人类IgM(+)IgD(+)CD27(+) B细胞的记忆B细胞特征，即它们与IgG(+) GC后B细胞共享典型的记忆B细胞转录模式，并表现出更快、更强的再刺激潜能，这是免疫记忆的一个标志。此外，这项工作揭示了人类IgM记忆B细胞的功能可塑性，这不仅表现在它们在重新激活时易于经历二次GC反应，还表现在它们通过与免疫调节性中性粒细胞相互作用在早期炎症中发挥的特殊作用。
