Following stimulation, primary B cells either directly undergo terminal differentiation to IgM-secreting plasma cells or enter the memory pathway characterized by affinity maturation and isotype switching. Which of the various fates is adopted by B cells is determined by the strength and duration of the antigenic signal, the availability and quality of T cell help and additional signals derived from the germinal center milieu. High rate secretion is correlated with endogenous Blimp-1 levels and can be caused by ectopic expression of Blimp-1. Using cultures of resting primary mouse B cells stimulated in vitro in various combinations with IL-4, anti-mu F(ab')2 or anti-CD40 in the absence or presence of lipopolysaccharide, we show that IgM secretion and the expression of Blimp-1 is either not induced or even suppressed by B cell receptors (BCR) or CD40 ligation and by IL-4. Additional treatment with IL-2 and IL-5 induces Blimp-1 expression and facilitates IgM and IgG1 secretion, which can also be achieved by retroviral transduction of Blimp-1. On the other hand, the drastic increase in membrane IgG1(+) cells with time in cultures treated with IL-4 is greatly diminished in cells forced to express Blimp-1. We conclude that suppression of Blimp-1 by antigen-BCR interaction and T helper cell-dependent CD40 and IL-4 signaling are necessary to facilitate entrance into the memory pathway and to prevent terminal differentiation.