Background Understanding key signals that control the differentiation, function, and survival of plasma cells (PCs) is critical for development of improved therapeutic approaches to attenuate pathogenic antibody responses in SLE. While phosphatidylinositide 3-kinase delta (PI3Kδ) plays an essential role in humoral immune responses, its role(s) in PC function remains poorly understood.
Methods We utilized a conditional mouse model of Activated PI3Kδ Syndrome (APDS), to interrogate the role of this key signaling program.
Results Mice expressing a gain-of-function mutation in PIK3CD in B cells, referred to as activated (a) PIK3CD, generated increased numbers of memory B cells, mounted enhanced secondary response, yet exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation. Remarkably, PC specific aPIK3CD expression was sufficient to diminish humoral responses in vivo. Mechanistically, aPIK3CD disrupted endoplasmic reticulum proteostasis and autophagy, leading to increased PC death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3Kδ-specific inhibitors.
Conclusions Taken together, these data demonstrate an unexpected requirement to down-regulate PI3Kδ activity to balance autophagy and the unfolded protein response, events essential to modulate ER stress and ensure PC survival. Thus, enhancing PI3Kδ activity may provide a novel means to trigger early PC death and dampen autoantibody responses.
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