title: The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions.
abstract: Effector memory (EM) CD4(+) T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4(+) T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4(+) T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4(+) T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4(+) T cells in normoxic and hypoxic conditions.
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; sarah.dimeloe@unibas.ch chess@uhbs.ch.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dimeloe
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich, 4058 Basel, Switzerland;
authors.forename: Matthias
authors.initials: M
authors.lastname: Mehling
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Corina
authors.initials: C
authors.lastname: Frick
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Jordan
authors.identifier: http://orcid.org/0000-0001-8826-9730
authors.initials: J
authors.lastname: Loeliger
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Bantug
authors.affiliation: Microscopy Center, Biocenter, University of Basel, 4056 Basel, Switzerland; and.
authors.forename: Ursula
authors.initials: U
authors.lastname: Sauder
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Marco
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Réka
authors.initials: R
authors.lastname: Belle
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland;
authors.forename: Leyla
authors.initials: L
authors.lastname: Develioglu
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich, 4058 Basel, Switzerland;
authors.forename: Savaş
authors.initials: S
authors.lastname: Tay
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Langenkamp
authors.affiliation: Immunobiology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; sarah.dimeloe@unibas.ch chess@uhbs.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015687:Cell Hypoxia / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival / Q000276:immunology; D005947:Glucose / Q000378:metabolism*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial; D044085:Microfluidics; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D019289:Pyruvic Acid; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D005947:Glucose; D010100:Oxygen