Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress |
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| Authors: | Fahd Al Qureshah Sara Sagadiev Christopher D. Thouvenel Shuozhi Liu Zhaolin Hua Baidong Hou Mridu Acharya Richard G. James David J. Rawlings |
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| Affiliation: | 1. Center for Immunity and Immunotherapy, Seattle Children’s Research Institute, Seattle, WA ; 2. Departments of Immunology, University of Washington, Seattle, WA ; 3. King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia ; 4. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China ; 5. Departments of Pediatrics, University of Washington, Seattle, WA ; 6. Departments of Pharmacology, University of Washington, Seattle, WA |
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| Abstract: | While phosphatidylinositide 3-kinase delta (PI3Kδ) plays a critical role in humoral immunity, the requirement for PI3Kδ signaling in plasma cells remains poorly understood. Here, we used a conditional mouse model of activated PI3Kδ syndrome (APDS), to interrogate the function of PI3Kδ 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 PI3Kδ-specific inhibitors. Our findings establish an essential role for PI3Kδ in plasma cell homeostasis and suggest that modulating PI3Kδ activity may be useful for promoting and/or thwarting specific immune responses. |
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