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

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

doi:10.1016/j.celrep.2021.109804

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

Cell Rep. 2021 Oct 12;37(2):109804. doi: 10.1016/j.celrep.2021.109804.

Authors

Jennifer L Cannons¹, Alejandro V Villarino², Senta M Kapnick³, Silvia Preite⁴, Han-Yu Shih⁵, Julio Gomez-Rodriguez⁶, Zenia Kaul⁷, Hirofumi Shibata⁷, Julie M Reilley⁴, Bonnie Huang⁴, Robin Handon⁸, Ian T McBain⁷, Selamawit Gossa⁹, Tuoqi Wu¹⁰, Helen C Su⁷, Dorian B McGavern⁹, John J O'Shea¹¹, Peter J McGuire⁸, Gulbu Uzel⁷, Pamela L Schwartzberg¹²

Affiliations

¹ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
² National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA; Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
³ National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
⁴ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁵ National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA; National Eye Institute, NIH, Bethesda, MD 20892, USA.
⁶ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; TCR2 Therapeutics, Cambridge, MA 02142, USA.
⁷ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁸ National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁹ National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
¹⁰ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; University of Colorado, Department of Immunology, Denver, CO 80204, USA; Department of Immunology and Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390.
¹¹ National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
¹² National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

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, Pik3cd^E1020K/+ 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, Pik3cd^E1020K/+ CD8⁺ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cd^E1020K/+ 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.

Keywords: CD8 T cell memory; IL-2; Myc; Phosphatidylinositide 3 Kinase delta (PI3Kδ); TCF1; apoptosis; effector T cells; long-lived effector cells (LLEC); mTOR; metabolism.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

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

Substances

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

Supplementary concepts

Activated PI3K-delta Syndrome

Grants and funding

ZIA AI001240/ImNIH/Intramural NIH HHS/United States