Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells.
Germinal center (GC) B cells undergo somatic hypermutation, class switch recombination, and rapid clonal expansion to produce high-affinity antibodies. The BCL6 transcriptional repressor facilitates this phenotype because it can repress DNA damage checkpoint genes. GC B and T cells can make transient direct physical contact; T cells were observed to be associated with dead B-cell fragments. We thus hypothesized that one function of CD40 signaling from T cells within this timeframe could be to modulate BCL6 activity. CD40 signaling rapidly disrupts the ability of BCL6 to recruit the SMRT corepressor complex by excluding it from the nucleus, leading to histone acetylation, RNA polymerase II processivity, and activation of BCL6 target genes, such as CD23b, ATR, and TP53. Washout of CD40 to emulate transient T-cell contact permitted BCL6 target gene mRNA levels to return to their repressed levels, demonstrating that this is a reversible process, which could allow centroblasts that pass quality control to either continue proliferation or undergo terminal differentiation. These data suggest that transient CD40 signaling in the GC might allow T cells to weed out heavily damaged centroblasts while at the same time promoting survival of intact B cells, which could undergo differentiation or additional rounds of proliferation.
Polo
Jose M
JM
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Ci
Weimin
W
Licht
Jonathan D
JD
Melnick
Ari
A
D021581:Active Transport, Cell Nucleus; D001402:B-Lymphocytes / Q000473:pathology*; D019013:CD40 Antigens / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2; D014066:Palatine Tonsil; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction
D019013:CD40 Antigens; D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D012097:Repressor Proteins