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

Abstract 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 poorly understood. Using APDS 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, associated with increased Fas-mediated apoptosis due to sustained phosphorylation of FoxO1 and derepression of FasL. In addition, Pik3cdE1020K/+ CD8+ T cells exhibit enhanced mTORC1 and c-Myc signatures; metabolic perturbations; and reorientation of their chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ T cells failed to sustain expression of proteins critical for maintenance of long-lived memory cells, including TCF1. 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 driver integrating multiple signaling circuits that promote terminal CD8+ T cell effector differentiation at the expense of memory and long-lived T cell responses. This work was funded in part by the Intramural Research Program of NIAID, NIH.