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

Bertram Bengsch, Andy L. Johnson, Makoto Kurachi, Pamela M. Odorizzi, Kristen E. Pauken, John Attanasio, Erietta Stelekati, Laura M. McLane, Michael A. Paley, Greg M. Delgoffe, E. John Wherry

Research output: Contribution to journalArticlepeer-review

222 Scopus citations

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.

Original languageEnglish
Pages (from-to)358-373
Number of pages16
JournalImmunity
Volume45
Issue number2
DOIs
StatePublished - 2016

Fingerprint Dive into the research topics of 'Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8<sup>+</sup> T Cell Exhaustion'. Together they form a unique fingerprint.

Cite this