title: Phosphatidylinositol 3-Kinase p110δ Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections.
abstract: The p110δ isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110δ-deficient CD8(+) T cells, we demonstrated a critical role for the p110δ subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110δ signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110δ signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110δ in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110δ signaling in in vivo CD8(+) T cell immunity to microbial pathogens.
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129;
authors.forename: Donald T
authors.identifier: http://orcid.org/0000-0002-3142-9059
authors.initials: DT
authors.lastname: Gracias
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129;
authors.forename: Alina C
authors.identifier: http://orcid.org/0000-0001-7176-1809
authors.initials: AC
authors.lastname: Boesteanu
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Joseph A
authors.identifier: http://orcid.org/0000-0001-7900-8993
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and.
authors.forename: Jennifer L
authors.identifier: http://orcid.org/0000-0002-2363-5442
authors.initials: JL
authors.lastname: Hope
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19129.
authors.forename: Alison J
authors.identifier: http://orcid.org/0000-0001-7610-5659
authors.initials: AJ
authors.lastname: Carey
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and.
authors.forename: Yvonne M
authors.identifier: http://orcid.org/0000-0002-4654-7509
authors.initials: YM
authors.lastname: Mueller
authors.affiliation: Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Omkar U
authors.initials: OU
authors.lastname: Kawalekar
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129;
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Fike
authors.affiliation: Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Carl H
authors.identifier: http://orcid.org/0000-0003-0241-3557
authors.initials: CH
authors.lastname: June
authors.affiliation: Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and p.katsikis@erasmusmc.nl.
authors.forename: Peter D
authors.identifier: http://orcid.org/0000-0001-7690-5218
authors.initials: PD
authors.lastname: Katsikis
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014777:Virus Diseases / Q000201:enzymology* / Q000276:immunology
chemical_list: D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases