1. PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8 + T cells at the expense of central memory.
- Author
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Cannons JL, Villarino AV, Kapnick SM, Preite S, Shih HY, Gomez-Rodriguez J, Kaul Z, Shibata H, Reilley JM, Huang B, Handon R, McBain IT, Gossa S, Wu T, Su HC, McGavern DB, O'Shea JJ, McGuire PJ, Uzel G, and Schwartzberg PL
- Subjects
- Adolescent, Adult, Animals, Apoptosis, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Case-Control Studies, Child, Chromatin genetics, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases immunology, Disease Models, Animal, Enzyme Activation, Fas Ligand Protein genetics, Fas Ligand Protein metabolism, Female, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases immunology, Signal Transduction, Virus Diseases genetics, Virus Diseases immunology, Mice, CD8-Positive T-Lymphocytes enzymology, Chromatin metabolism, Chromatin Assembly and Disassembly, Class I Phosphatidylinositol 3-Kinases metabolism, Immunologic Memory, Primary Immunodeficiency Diseases enzymology, Transcription, Genetic, Virus Diseases enzymology
- 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, 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., Competing Interests: Declaration of interests S.P. is an employee of AstraZeneca and may own stock or stock options. J.G.-R. is an employee of TCR2. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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