PI3Kd coordinates transcriptional, epigenetic and metabolic changes to promote effector CD8+ T cells differentiation at the expense of memory.

Patients with Activated-PI3Kd Syndrome (APDS) present with sinopulmonary infections, lymphadenopathy and CMV and/or EBV viremia, yet why patients fail to clear certain viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of short-lived effectors both in vitro and post-viral infection, including increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and derepression of FasL. Activated Pik3cdE1020K/+ CD8+ T cells displayed enhanced mTORC1 and c-Myc signatures, accompanied by metabolic perturbations linked to an accelerated effector program. Conversely, Pik3cdE1020K/+ CD8+ T cells failed to sustain expression of proteins critical for maintenance of long-lived memory cells, including TCF1, and mounted inadequate memory responses in vivo. Strikingly, activated Pik3cdE1020K/+ CD8+ T cells exhibit altered transcriptional and epigenetic circuits characterized by a pronounced IL-2/STAT5 signature associated with heightened IL-2 responses that prevented differentiation to memory-like cells in the presence of IL-15. Our data position PI3Kd as a central hub integrating multiple signaling nodes that promote terminal CD8+ T cell effector differentiation at the expense of memory and long-lived T cell responses. Overall design: Integrated analysis of RNA-seq and ATAC-seq data from Wild-type and Pik3cdE1020K/+ CD8+ cells.