CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells
CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells
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DOI：
10.4049/jimmunol.0804272
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发表时间：
2009-06-15
影响因子：
4.4
通讯作者：
Fest, Thierry
中科院分区：
文献类型：
--
作者：
Caron, Gersende;Le Gallou, Simon;Fest, Thierry
人类生发中心是一个高度动态的结构，B 细胞在此按照趋化因子梯度进行终末分化和运输。快速分裂的中心母细胞和不分裂的中心细胞代表生发中心中存在的两个主要 B 细胞亚群，也是大多数淋巴瘤最常见的正常对应细胞。 CD77 表达以前与经历体细胞超突变的增殖中心母细胞相关，但转录研究的数据表明 CD77 并不是区分人类中心母细胞和中心细胞的可靠标记。在此，我们首次能够根据趋化因子受体 CXCR4 的表达来区分这两个亚群，从而对其进行表征。特别探讨了表型和功能特征，给出了 CXCR4(+) 中心母细胞的准确定义；与CXCR4(-)中心细胞相比。我们发现CXCR4(+)和CXCR4(-)生发中心B细胞在增殖、转录因子表达、Ig产生和体细胞超突变调控方面呈现出明显的二分性。微阵列分析确定了分离这些 B 细胞的广泛基因列表，其中包括根据先前知识高度相关的基因。通过基因集富集分析，我们证明了伯基特淋巴瘤中中央母细胞基因表达特征显着富集。总的来说，我们的研究结果表明，CXCR4 表达可以正确地将人中心母细胞与中心细胞分开，并为纯化成熟 B 细胞来源的恶性肿瘤的正常对应物提供了可能性。免疫学杂志，2009，182：7595-7602。
The human germinal center is a highly dynamic structure where B cells conduct their terminal differentiation and traffic following chemokine gradients. The rapidly dividing centroblasts and the nondividing centrocytes represent the two major B cell subsets present in germinal center and also the most common normal counterparts for a majority of lymphomas. CD77 expression was previously associated to proliferating centroblasts undergoing somatic hypermutation, but data from transcriptional studies demonstrate that CD77 is not a reliable marker to discriminate human centroblasts from centrocytes. Herein we were able for the first time to separate these two subpopulations based on the expression of the chemokine receptor CXCR4 allowing their characterization. Phenotypic and functional features were especially explored, giving an accurate definition of CXCR4(+) centroblasts; compared with CXCR4(-) centrocytes. We show that CXCR4(+) and CXCR4(-) germinal center B cells present a clear dichotomy in terms of proliferation, transcription factor expression, Ig production, and somatic hypermutation regulation. Microarray analysis identified an extensive gene list segregating these B cells, including highly relevant genes according to previous knowledge. By gene set enrichment analysis we demonstrated that the centroblastic gene expression signature was significantly enriched in Burkitt's lymphomas. Collectively, our findings show that CXCR4 expression can properly separate human centroblasts from centrocytes and offer now the possibility to have purified normal counterparts of mature B cell-derived malignancies. The Journal of Immunology, 2009, 182: 7595-7602.