[PDF][PDF] Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion

B Bengsch, AL Johnson, M Kurachi, PM Odorizzi… - immunity, 2016 - cell.com
B Bengsch, AL Johnson, M Kurachi, PM Odorizzi, KE Pauken, J Attanasio, E Stelekati…
immunity, 2016cell.com
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 …
Summary
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.
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