Suppression of Phosphatidylinositol 3,4,5-Trisphosphate Production Is a Key Determinant of B Cell Anergy

Anergy is a critical physiologic mechanism to censor self-reactive B cells. However, a biochemical understanding of how anergy is achieved and maintained is lacking. Herein, we investigated the role of the phosphoinositide 3-kinase (PI3K) lipid product PI(3,4,5)P-3 in B cell anergy. We found reduced generation of PI(3,4,5)P-3 in anergic B cells, which was attributable to reduced phosphorylation of the PI3K membrane adaptor CD19, as well as increased expression of the inositol phosphatase II Sustained production of PI(3,4,5)P3 in B cells, achieved through conditional deletion of Pten, resulted in failed tolerance induction and abundant autoantibody production. In contrast to wild-type immature B cells, B cell receptor engagement of PTEN-deficient immature B cells resulted in activation and proliferation, indicating a central defect in early B cell responsiveness. These findings establish repression of the PI3K signaling pathway as a necessary condition to avert the generation, activation, and persistence of self-reactive B cells.