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. Epub 2016 Aug 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • B7-H1 Antigen / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cellular Reprogramming
  • Cellular Senescence
  • Energy Metabolism
  • Glucose / metabolism
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antibodies, Neutralizing
  • B7-H1 Antigen
  • Pdcd1 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Programmed Cell Death 1 Receptor
  • TOR Serine-Threonine Kinases
  • Glucose