Transitional B cells exhibit a B cell receptor-specific nuclear defect in gene transcription.
The signaling programs that enforce negative selection in early transitional (T1) B cells in response to BCR engagement remain poorly defined. We conducted a comprehensive comparison of BCR signaling in T1 vs follicular mature splenic B cells. T1, in contrast to follicular mature B cells, failed to express key NF-kappaB target genes in response to BCR engagement and exhibited a striking defect in assembly of an active transcriptional complex at the promoter of the survival and proliferative genes A1 and c-Myc. Surprisingly, and contrary to previous models, classical protein kinase C and IkappaB kinase activation, NF-kappaB nuclear translocation and DNA binding were intact in T1 B cells. Furthermore, despite a marked reduction in NFAT1 expression, differential NFAT or AP-1 activation cannot explain this transcriptional defect. Our combined findings demonstrate that T1 B cells are programmed for signal- and stage-specific "nuclear nonresponsiveness" upon encounter with self-Ags.
Andrews
Sarah F
SF
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Rawlings
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D018448:Models, Immunological; D050778:NFATC Transcription Factors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*
C096816:BCL2-related protein A1; D018985:Epitopes, B-Lymphocyte; D015778:Minor Histocompatibility Antigens; C489428:Myc protein, mouse; D050778:NFATC Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell