Stage-specific modulation of IFN-Regulatory factor 4 function by Kruppel-type zinc finger proteins

Optimal humoral responses depend on the activation of Ag-specific B cells, followed by their progression toward a fully differentiated phenotype. Acqu isition of stage-appropriate patterns of gene expression is crucial to this differentiation program. However, the molecular mechanisms used by B cells to modulate gene expression as they complete their maturation program are poorly understood. IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonst rated that IRF-4 is induced in response to B cell-activating stimuli and th at it acts as a transactivator of CD23 gene expression. We have furthermore found that IRF-4 function can be blocked by B cell lymphomas 6 (BCL-6) pro tein, a Kruppel-type zinc finger repressor normally expressed in germinal c enter B cells. However, CD23 expression is known to be down-regulated in pl asma cells despite high level expression of IRF-4 and the lack of BCL-6, su ggesting that in plasma cells the IRF-4-mediated induction of CD23 is preve nted by its interaction with a distinct repressor. In this set of studies, we demonstrate that IRF-4 interacts with B lymphocyte-induced maturation pr otein/positive regulatory domain I-binding factor 1 (Blimp1/PRD1-BF1), a Kr uppel-type zinc finger protein whose expression correlates with terminal B cell differentiation. Functional studies indicate that Blimp1, like BCL-6, can block IRF-4-transactivating ability. These findings thus support a mode l whereby IRF-4 function is modulated in a stage-specific manner by its int eraction with developmentally restricted sets of Kruppel-type zinc finger p roteins.