Cell Reports
Volume 16, Issue 5, 2 August 2016, Pages 1243-1252
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Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host

https://doi.org/10.1016/j.celrep.2016.06.078Get rights and content
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Highlights

  • Exhausted CD8 T cells show increased expression of glucose transporter-1

  • Functional, but not exhausted, T cells can use OXPHOS to supplement their energy demand

  • Exhausted T cells harbor dysfunctional depolarized mitochondria

  • Interleukin-12 can rescue mitochondrial function and effector responses in exhausted CD8

Summary

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.

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