Blimp-1 over-expression abrogates IL-4-and CD40-mediated suppression of terminal B cell differentiation but arrests isotype switching

Following stimulation, primary B cells either directly undergo terminal dif ferentiation to IgM-secreting plasma: cells or enter the memory pathway cha racterized by affinity maturation and isotype switching. Which of the vario us 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 ad ditional signals derived from the germinal center milieu. High rate secreti on is correlated with endogenous Blimp-1 levels and can be caused by ectopi c expression of Blimp-1. Using cultures of resting primary mouse B cells st imulated in vitro in various combinations with IL-4, anti-mu F(ab')(2) or a nti-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 supp ressed by B cell receptors (BCR) or CD40 ligation and by IL-4, Additional t reatment with IL-2 and IL-5 induces Blimp-1 expression and facilitates IgM and IgG1 secretion, which can also be achieved by retroviral transduction o f Blimp-1. On the other hand, the drastic increase in membrane IgG1(+) cell s with time in cultures treated with IL-4 is greatly diminished in cells fo rced 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 ne cessary to facilitate entrance into the memory pathway and to prevent termi nal differentiation.