bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells.
Immunization with T cell-dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2-transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.
Smith
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KG
The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria 3050, Australia.
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O'Reilly
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Ang
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Strasser
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Tarlinton
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D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D015870:Gene Expression; D019254:Genes, bcl-2; D018858:Germinal Center / Q000502:physiology*; D007114:Immunization; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009244:NAD+ Nucleosidase / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1