Seifert Marc, Küppers Ralf
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, D-45122 Essen, Germany.
J Exp Med. 2009 Nov 23;206(12):2659-69. doi: 10.1084/jem.20091087. Epub 2009 Nov 16.
The origin of IgM(+)CD27(+) B lymphocytes with mutated IgV genes, which account for approximately 20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell-independent immune responses, or in T cell-dependent germinal center (GC) reactions has been proposed. We show here that IgM(+)IgD(+)CD27(+) and IgM(+)IgD(-/low)CD27(+) B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM(+)IgD(+)CD27(+) B cells clonally related to GC-derived IgG(+) memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically mutated IgM(+) B cells and indicate that adult humans harbor a large population of IgM(+)IgD(+) post-GC memory B cells. Furthermore, the analysis revealed that a highly diverse and often very large population of memory B cells is generated from a given GC B cell clone, and that (preferentially IgM) memory B cells are generated already early in the GC reaction. This provides novel insights into the dynamics of GC reactions and the generation of a memory B cell repertoire.
IgV基因发生突变的IgM(+)CD27(+) B淋巴细胞约占人类外周血（PB）B细胞的20%，其来源一直存在争议。有人提出它们产生于初级多样化途径、非T细胞依赖性免疫反应或T细胞依赖性生发中心（GC）反应中。我们在此表明，IgM(+)IgD(+)CD27(+)和IgM(+)IgD(-/低)CD27(+) B细胞亚群，如同类别转换记忆B细胞一样，携带Bcl6基因突变，这是GC经历的一种遗传特征。此外，鉴定出与GC来源的IgG(+)记忆B细胞克隆相关的PB IgM(+)IgD(+)CD27(+) B细胞，它们具有共享和独特的IgV基因突变，这也证明了前一个亚群同样起源于GC。这些发现为体细胞突变的IgM(+) B细胞来源于GC提供了遗传学证据，并表明成年人体内存在大量GC后IgM(+)IgD(+)记忆B细胞。此外，分析显示，给定的GC B细胞克隆可产生高度多样化且通常数量非常庞大的记忆B细胞群体，并且（优先为IgM）记忆B细胞在GC反应早期就已产生。这为GC反应的动力学和记忆B细胞库的产生提供了新的见解。
