title: Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host.
abstract: T cells undergo profound metabolic changes to meet the increased energy demands of maintaining an antiviral response. We postulated that differences in metabolic reprogramming would shape the efficacy of CD8 T cells mounted against persistent viral infections. We found that the poorly functional PD-1(hi) T cell response against hepatitis B virus (HBV) had upregulated the glucose transporter, Glut1, an effect recapitulated by oxygen deprivation to mimic the intrahepatic environment. Glut1(hi) HBV-specific T cells were dependent on glucose supplies, unlike the more functional cytomegalovirus (CMV)-specific T cells that could utilize oxidative phosphorylation in the absence of glucose. The inability of HBV-specific T cells to switch to oxidative phosphorylation was accompanied by increased mitochondrial size and lower mitochondrial potential, indicative of mitochondrial dysfunction. Interleukin (IL)-12, which recovers HBV-specific T cell effector function, increased their mitochondrial potential and reduced their dependence on glycolysis. Our findings suggest that mitochondrial defects limit the metabolic plasticity of exhausted HBV-specific T cells.
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK. Electronic address: a.schurich@ucl.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pallett
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK.
authors.forename: Danyal
authors.initials: D
authors.lastname: Jajbhay
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wijngaarden
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK.
authors.forename: Itziar
authors.initials: I
authors.lastname: Otano
authors.affiliation: Hepatology Unit, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Upkar S
authors.initials: US
authors.lastname: Gill
authors.affiliation: Hepatology Unit, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Navjyot
authors.initials: N
authors.lastname: Hansi
authors.affiliation: Hepatology Unit, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Kennedy
authors.affiliation: Department of Clinical Virology, University College London Hospital, London WC1N 1EH, UK; Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Nastouli
authors.affiliation: Research Department of Infection and Population Health, University College London, London WC1E 6JB, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Sian M
authors.initials: SM
authors.lastname: Henson
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6JF, UK.
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology* / Q000821:virology*; D003587:Cytomegalovirus / Q000472:pathogenicity; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology / Q000821:virology; D010085:Oxidative Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D014777:Virus Diseases / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D061026:Programmed Cell Death 1 Receptor; D018664:Interleukin-12; D005947:Glucose