PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8⁺ T cells at the expense of central memory.

ABSTRACT: Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cd^E1020K/+ mice), we demonstrate that, upon activation, Pik3cd^E1020K/+ CD8⁺ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cd

SUBMITTER: Cannons JL 

PROVIDER: S-EPMC8582080 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature