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

• DOI: 10.1016/j.celrep.2021.109804
• Publication Date: 2021-10-13T14:14:35Z
• Authors: Jennifer L. Cannons; Alejandro V. Vill...; Senta M. Kapnick; Silvia Preite; Han-Yu Shih; Julio Gomez-Rodri...; Zenia Kaul; Hirofumi Shibata; Julie M. Reilley; Bonnie Huang; Robin Handon; Ian T. McBain; Selamawit Gossa; Tuoqi Wu; Helen C. Su; Dorian B. McGavern; John J. O’Shea; Peter J. McGuire; Gulbu Uzel; Pamela L. Schwart...
• Keywords: Adult; Male; Mice, Knockout; 0301 basic medicine; Fas Ligand Protein; Adolescent; Class I Phosphatidylinositol 3-Kinases; Apoptosis; CD8-Positive T-Lymphocytes; Chromatin Assembly and Disassembly; Article; Chromatin; 3. Good health; Enzyme Activation; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; HEK293 Cells; Case-Control Studies; Animals; Humans; Female; Child; Immunologic Memory

Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present 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 a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro after infection that are associated increased Fas-mediated apoptosis due sustained FoxO1 phosphorylation Fasl derepression, enhanced mTORC1 c-Myc signatures, metabolic perturbations, an altered chromatin landscape. Conversely, sustain expression proteins critical for central memory, including TCF1. Strikingly, transcriptional epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures heightened IL-2 responses prevent differentiation memory-like IL-15. Our data position PI3Kδ as integrating multiple signaling nodes promote cell differentiation, providing insight into phenotypes APDS.