Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD 1 Are an Early Driver of CD8( T Cell Exhaustion.
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 1a. Improving bioenergetics by overexpression of PGC 1a 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.
Immunity