@article{4c46d03a7fee4d16b7b768f58418e70b,
title = "Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8+ T Cell Exhaustion",
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.",
author = "Bertram Bengsch and Johnson, {Andy L.} and Makoto Kurachi and Odorizzi, {Pamela M.} and Pauken, {Kristen E.} and John Attanasio and Erietta Stelekati and McLane, {Laura M.} and Paley, {Michael A.} and Delgoffe, {Greg M.} and Wherry, {E. John}",
note = "Funding Information: We thank J.-E. Lee and K. Foskett for help with flux analyses, M. Reuter for help with the Imagestream, D. Williams, for electron microscopy, M. Bohnert for sharing her mitochondrial expertise, and J. Kurachi for technical support. Tetramers were obtained from the NIH tetramer core. B.B. was supported by German Research Foundation fellowship BE5496/1-1, G.M.D. by the Sidney Kimmel Foundation for Cancer Research (SKF-015-039), the Samuel and Emma Winters Foundation, and the NIH (P50CA121973 Skin Cancer SPORE), K.E.P. by a Robertson Foundation/Cancer Research Institute Irvington Fellowship and A.L.J. by a Philadelphia Foundation{\textquoteright}s Brody Family Medical Trust Fund fellowship. This work was supported by NIH grants AI105343, AI082630, AI095608, AI112521, AI115712, AI117718, AI108545, and AI2010085 to E.J.W. This research was supported by the Parker Institute for Cancer Immunotherapy. E.J.W. has a patent licensing agreement on the PD-1 pathway. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
doi = "10.1016/j.immuni.2016.07.008",
language = "English",
volume = "45",
pages = "358--373",
journal = "Immunity",
issn = "1074-7613",
number = "2",
}