| First Author | Bengsch B | Year | 2016 |
| Journal | Immunity | Volume | 45 |
| Issue | 2 | Pages | 358-73 |
| PubMed ID | 27496729 | Mgi Jnum | J:258882 |
| Mgi Id | MGI:6141407 | Doi | 10.1016/j.immuni.2016.07.008 |
| Citation | Bengsch B, et al. (2016) Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45(2):358-73 |
| abstractText | 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-1alpha. Improving bioenergetics by overexpression of PGC-1alpha 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. |
