Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation.
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.
Seifert
Marc
M
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, D-45122 Essen, Germany.
Küppers
Ralf
R
D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D013601:T-Lymphocytes / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology*
C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D051560:Proto-Oncogene Proteins c-bcl-6; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7