Transcriptional Regulation of Germinal Center B and Plasma Cell Fates by Dynamical Control of IRF4

The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression invivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 cobound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations, IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of "kinetic control" in which signaling-induced dynamics of IRF4 in activated B cells control their cell-fate outcomes. •IRF4 regulates GC B cell differentiation by directly activating Bcl6 and Obf1•IRF4 cellular concentrations orchestrate antigen-induced B cell fates•Occupancy of ISRE motif correlates with high cellular concentrations of IRF4•ISRE motifs are enriched in plasma cell genes.