Induction of high Bcl6 expression and its roles in germinal center B cells

The Bcl6 proto-oncogene, which encodes a transcriptional repressor, is predominantly expressed in germinal center (GC) B cells. However, inducers of its high expression in GC B cells and a role for Bcl6 in GC B cells were largely unknown. Here we examined transcriptional regulation of the murine Bcl6 gene. JunD/AP-1 was the major enhancer molecule in GC-derived B lymphoma cells. In addition, we identified the silencer region in the promoter and Bcl6 bound to the silencer region. Activated STATs also bound to the silencer region and competed with Bcl6 for the binding. STAT3 was the major STATs activated in GC B cells. Thus, JunD/AP-1 and STAT3 drive high Bcl6 expression in GC B cells. Since stimulation of splenic B cells with IL-21 induced high Bcl6 expression with STAT3 activation and junD induction, IL-21 may well be a major inducer for high Bcl6 expression in GC B cells. IL-21 stimulation of naive B cells induces their apoptosis, and Bcl6-dedicient B cells are more sensitive to IL-21-induced apoptosis. Thus, Bcl6 induced in activated B cells by IL-21 stimulation protects these B cells from the apoptosis, and these B cells may differentiate into GC B cells.