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Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, D-45122 Essen, Germany

CORRESPONDENCE Ralf Küppers: ralf.kueppers{at}uk-essen.de

The origin of IgM⁺CD27⁺ B lymphocytes with mutated IgV genes, which account for 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^–/lowCD27⁺ 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.

Abbreviations used: BCR, B cell receptor; CDR, complementarity determining region; FR, framework region; GC, germinal center; MMC, major mutation cluster; PB, peripheral blood; SHM, somatic hypermutation; SNP, single-nucleotide polymorphism; TD, T cell dependent; TI, T cell independent.

© 2009 Seifert and Küppers
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