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

  • Immunity. 2016 Aug 16;45(2):358-73. doi: 10.1016/j.immuni.2016.07.008.
Bertram Bengsch  1 ,  Andy L Johnson  1 ,  Makoto Kurachi  1 ,  Pamela M Odorizzi  1 ,  Kristen E Pauken  1 ,  John Attanasio  1 ,  Erietta Stelekati  1 ,  Laura M McLane  1 ,  Michael A Paley  1 ,  Greg M Delgoffe  2 ,  E John Wherry  3
Affiliations
  • 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: [email protected].
PMID: 27496729 DOI: 10.1016/j.immuni.2016.07.008
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.