Activated PI3K8 signals compromise plasma cell survival via limiting autophagy and increasing ER stress

While phosphatidylinositide 3-kinase delta (PI3K8) plays a critical role in humoral immunity, the requirement for PI3K8 signaling in plasma cells remains poorly understood. Here, we used a conditional mouse model of activated PI3K8 syndrome (APDS), to interrogate the function of PI3K8 in plasma cell biology. Mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) in B cells generated increased numbers of memory B cells and mounted an enhanced secondary response but exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation, and expression of aPIK3CD intrinsically in plasma cells was sufficient to diminish humoral responses. Mechanistically, aPIK3CD disrupted ER proteostasis and autophagy, which led to increased plasma cell death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3K8-specific inhibitors. Our findings establish an essential role for PI3K8 in plasma cell homeostasis and suggest that modulating PI3K8 activity may be useful for promoting and/or thwarting specific immune responses.