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 (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ 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, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS.

• Authors: Jennifer L Cannons, Alejandro V Villarino, Senta M Kapnick, Silvia Preite, Han-Yu Shih, Julio Gomez-Rodriguez, 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 Schwartzberg
• Journal: Cell reports (Cell Rep) Vol. 37 Issue 2 Pg. 109804 (10 12 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34644563 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• FASLG protein, human
• Fas Ligand Protein
• Fasl protein, mouse
• Class I Phosphatidylinositol 3-Kinases
• PIK3CD protein, human
• Pik3cd protein, mouse

Topics

• Adolescent
• Adult
• Animals
• Apoptosis
• CD8-Positive T-Lymphocytes (enzymology, immunology, virology)
• Case-Control Studies
• Child
• Chromatin (genetics, metabolism)
• Chromatin Assembly and Disassembly
• Class I Phosphatidylinositol 3-Kinases (genetics, immunology, metabolism)
• Disease Models, Animal
• Enzyme Activation
• Fas Ligand Protein (genetics, metabolism)
• Female
• HEK293 Cells
• Humans
• Immunologic Memory
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Primary Immunodeficiency Diseases (enzymology, genetics, immunology)
• Signal Transduction
• Transcription, Genetic
• Virus Diseases (enzymology, genetics, immunology)
• Mice