| First Author | Wenes M | Year | 2022 |
| Journal | Cell Metab | Volume | 34 |
| Issue | 5 | Pages | 731-746.e9 |
| PubMed ID | 35452600 | Mgi Jnum | J:328583 |
| Mgi Id | MGI:7286154 | Doi | 10.1016/j.cmet.2022.03.013 |
| Citation | Wenes M, et al. (2022) The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. Cell Metab 34(5):731-746.e9 |
| abstractText | Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8(+) T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8(+) T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8(+) T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses. |
