Activated PI3Kδ signaling in humoral immunity

Thesis (Ph.D.)--University of Washington, 2021p110δ, the catalytic subunit of phosphoinositide 3 kinase delta (PI3Kδ), is mainly expressed in immune cells and plays an important role in the development, activation, and differentiation of B cells. Gain-of-function mutations in PIK3CD, encoding the p110δ protein, cause a primary immunodeficiency disease called activated PI3Kδ syndrome (APDS). Affected individuals display a constellation of immune dysregulation and deficiency including lymphadenopathy, recurrent and chronic infection, increased IgM, impaired vaccine responses, and increased risk for lymphoma. While PI3Kδ plays a critical role in humoral immunity, the requirement for PI3Kδ signaling in plasma cells remains poorly understood. Here, we utilized a conditional mouse model of APDS to interrogate the function of PI3Kδ in plasma cell biology. Mice expressing a PIK3CD gain-of-function mutation (referred to as activated (a)PIK3CD) in B cells generated increased numbers of memory B cells and mounted 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 endoplasmic reticulum (ER) proteostasis and autophagy, which led to increased plasma cell death. Notably, this defect was driven primarily by elevated mTORC1 signaling and was 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