Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host.

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Schurich, Anna 
Pallett, Laura J 
Jajbhay, Danyal 
Wijngaarden, Jessica 
Otano, Itziar 

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.

Adolescent, Adult, CD8-Positive T-Lymphocytes, Cytomegalovirus, Female, Glucose, Glucose Transporter Type 1, Glycolysis, Hepatitis B virus, Humans, Interleukin-12, Male, Middle Aged, Mitochondria, Oxidative Phosphorylation, Programmed Cell Death 1 Receptor, Virus Diseases, Young Adult
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Cell Rep
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Elsevier BV
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Medical Research Council (MC_UU_12022/6)
A.S., J.W., and M.K.M. are funded by a Wellcome Trust Senior Investigator Award (to M.K.M.); L.J.P. and M.K.M. are funded by MRC Project grant no. MR/M020126/; I.O. is funded by an EASL post-doctoral fellowship; U.S.G. is funded by the Wellcome Trust Clinical Research Training Fellowship; and N.H. and P.T.K. are funded by a grant from Barts and The London Charity. A.S. was also funded by a UCLH CIDC/NIHR Fast Track Grant, and D.J. was funded by the Wolfson Foundation.