Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host
Anna Schurich,
Laura J. Pallett,
Danyal Jajbhay,
Jessica Wijngaarden,
Itziar Otano,
Upkar S. Gill,
Navjyot Hansi,
Patrick T. Kennedy,
Eleni Nastouli,
Richard Gilson,
Christian Frezza,
Sian M. Henson,
Mala K. Maini
Affiliations
Anna Schurich
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
Laura J. Pallett
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
Danyal Jajbhay
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
Jessica Wijngaarden
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
Itziar Otano
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
Upkar S. Gill
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
Navjyot Hansi
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
Patrick T. Kennedy
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
Eleni Nastouli
Department of Clinical Virology, University College London Hospital, London WC1N 1EH, UK
Richard Gilson
Research Department of Infection and Population Health, University College London, London WC1E 6JB, UK
Christian Frezza
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
Sian M. Henson
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
Mala K. Maini
Division of Infection and Immunity, University College London, London WC1E 6JF, UK
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-1hi 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. Glut1hi 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.
