title: Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function.
abstract: How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Balmer
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Ma
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Bantug
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Grählert
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Pfister
authors.affiliation: Proteomics Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Timo
authors.initials: T
authors.lastname: Glatter
authors.affiliation: Department of Biomedicine, Immunodeficiency, University of Basel, 4031 Basel, Switzerland.
authors.forename: Annaïse
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dimeloe
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dehio
authors.affiliation: Department of Biomedicine, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Krzyzaniak
authors.affiliation: Department of Biomedicine, Transplantation Immunology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Carolyn G
authors.initials: CG
authors.lastname: King
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Anne-Valérie
authors.initials: AV
authors.lastname: Burgener
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Leyla
authors.initials: L
authors.lastname: Develioglu
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Réka
authors.initials: R
authors.lastname: Belle
authors.affiliation: Department of Biomedicine, Immunodeficiency, University of Basel, 4031 Basel, Switzerland.
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.affiliation: Department of Biomedicine, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland.
authors.forename: Weldy V
authors.initials: WV
authors.lastname: Bonilla
authors.affiliation: Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, 3010 Bern, Switzerland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Macpherson
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3010 Bern, Switzerland.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hapfelmeier
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland. Electronic address: chess@uhbs.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism; D000085:Acetates / Q000378:metabolism*; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D006019:Glycolysis; D007113:Immunity, Innate; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D013312:Stress, Physiological / Q000276:immunology
chemical_list: D000085:Acetates; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; D001275:ATP Citrate (pro-S)-Lyase