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Immunity. 2016 Aug 16;45(2):358-73. doi: 10.1016/j.immuni.2016.07.008. Epub 2016 Aug 2.

Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion.

Author information

1
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
2
Tumor Microenvironment Center, Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
3
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA. Electronic address: wherry@mail.med.upenn.edu.

Abstract

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.

PMID:
27496729
PMCID:
PMC4988919
DOI:
10.1016/j.immuni.2016.07.008
[Indexed for MEDLINE]
Free PMC Article

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