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.