PI3K-Mediated Blimp-1 Activation Controls B Cell Selection and Homeostasis

Summary: Activation of phosphoinositide 3-kinase (PI3K) signaling plays a central role in regulating proliferation and survival of B cells. Here, we tested the hypothesis that B cell receptor (BCR)-mediated activation of PI3K induces the terminal differentiation factor Blimp-1 that interferes with proliferation and survival, thereby controlling the expansion of activated B cells. In fact, B-cell-specific inactivation of Pten, the negative regulator of PI3K signaling, leads to deregulated PI3K activity and elevated Blimp-1 expression. Combined deficiency for Pten and Blimp-1 results in abnormal expansion of B-1 B cells and splenomegaly. Interestingly, Blimp-1 also acts at early stages of B cell development to regulate B cell selection, as Blimp-1 deficiency results in an increased proportion of autoreactive B cells. Together, our data suggest that the combined requirement of deregulated PI3K signaling in addition to defective terminal differentiation represents the basis for proper selection and expansion of developing B cells. : Setz et al. show that BCR-mediated activation of PI3K induces the terminal differentiation factor Blimp-1 that interferes with cell cycling and survival, thereby preventing the expansion of activated B cells. Thus, the interplay between PI3K activity and regulation of terminal differentiation determines proper selection and expansion of developing B cells. Keywords: autoreactivity, proliferation, B cell development, selection, editing, clonal deletion differentiation, Pten, Blimp-