While PI3Kδ signaling is essential in immune cell function, the role of PI3Kδ in plasma cells remains poorly understood. To address this key question, Fahs and his team took advantage of the primary immunodeficiency disease APDS and generated a mouse model carrying a mutation causing the disease in patients. Their investigation revealed that elevated PI3Kδ signals impair the generation of plasma cells and diminish antibody production both in vivo and in vitro. Using RNA sequencing, electron microscopy, molecular, and cellular approaches, they show that activation of PI3Kδ signaling in B cells impairs autophagy, leading to increased ER stress and plasma cell death in an mTORC1-dependent mechanism. Notably, this defect was modulated by treatment with PI3Kδ-specific inhibitors.

The discovery provides a powerful tool in manipulating plasma cells which have been the focus of extensive research for decades because of their broad applications ranging from autoimmune and malignant diseases to vaccines and antibody production.