CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line.
CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line.
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DOI：
10.4049/jimmunol.160.5.2145
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发表时间：
1998-03
影响因子：
4.4
通讯作者：
Andrea Cerutti;H. Zan;András Schaffer;Leif Bergsagel;Nagaradona Harindranath;Edward E. Max;Paolo Casali
中科院分区：
文献类型：
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作者：
Andrea Cerutti;H. Zan;András Schaffer;Leif Bergsagel;Nagaradona Harindranath;Edward E. Max;Paolo Casali
生发中心的环境诱导B淋巴细胞进行Ig类转换和复杂的表型分化。部分原因是由于缺乏合适的体外B细胞模型，人类体内这些过程之间的关系在体外从未得到正式确立。我们已经鉴定出一株表达表面IgM和IGD的人B细胞株CL-01，在CD40配体、IL-4和IL-10的诱导下，它切换到所有七种下游同型，表现出典型的DNA开关重组，在目标CH区的胚系转录之前。在CL-01细胞中，开关诱导刺激引发表面IGD、CD23、CD38和CD77表达的伴随变化，与体外分离的扁桃体中心母细胞、中心细胞和记忆B细胞的表达相似。最终，在IL-6的存在下，CL-01细胞表达CD56并积聚胞浆中的免疫球蛋白G和免疫球蛋白A，这两种特性都是浆细胞样分化的特征。对分选的CL-01细胞中免疫球蛋白H基因的转录和重组分析表明，免疫球蛋白类转换始于中心母细胞，它延伸到中心细胞中的所有同型，在记忆B细胞中消失。因此，我们诱导了协调的Ig类转换，通过生发中心表型阶段的进展，并在单个B克隆型的水平上向记忆B细胞和浆细胞分化。我们的数据表明，这些过程可能受一个共同的成熟程序调控，该程序的激活可能只需要CD40配体、IL-4、IL-10和IL-6。
B lymphocytes are induced to undergo Ig class switching and a complex phenotypic differentiation by the milieu of the germinal center. Partly as a result of the lack of a suitable in vitro B cell model, the relationship between these processes in the humans has never been formally established in vitro. We have identified a human monoclonal B cell line, CL-01, that expresses surface IgM and IgD and, upon induction with CD40 ligand, IL-4, and IL-10, switches to all seven downstream isotypes, showing typical DNA switch recombination preceded by germline transcription of targeted CH regions. In CL-01 cells, switch-inducing stimuli trigger concomitant changes in expression of surface IgD, CD23, CD38, and CD77 that parallel those reported in ex vivo isolated tonsillar centroblasts, centrocytes, and memory B cells. Eventually, in the presence of IL-6, CL-01 cells express CD56 and accumulate cytoplasmic IgG and IgA, both traits of plasmacytoid differentiation. Analysis of transcription and recombination of the Ig H locus in sorted CL-01 cells suggest that Ig class switching begins in centroblasts, it extends to all isotypes in centrocytes, and it is extinct in memory B cells. Thus, we have induced coordinated Ig class switching, progression through germinal center phenotypic stages, and differentiation to memory B cells and plasma cells at the level of a single B clonotype. Our data suggest that these processes are likely regulated by a common maturation program, the activation of which may require CD40 ligand, IL-4, IL-10, and IL-6 only.