| Autor: |
Erica L. Braverman, Margaret A. McQuaid, Darlene A. Monlish, Andrea K. Dobbs, Manda J Ramsey, Archana Ramgopal, Harrison Brown, Craig A. Byersdorfer |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.10.01.510473 |
| Popis: |
T cell-based cellular therapies benefit from a product with reduced differentiation and enhanced oxidative metabolism. Methods to achieve this balance without negatively impacting T cell expansion or impairing T cell function have proven elusive. AMP-activated protein kinase (AMPK) is a cellular energy sensor which promotes mitochondrial health and improves oxidative metabolism. We hypothesized that increasing AMPK activity in human T cells would augment their oxidative capacity, creating an ideal product for adoptive cellular therapies. Lentiviral transduction of the regulatory AMPKγ2 subunit stably enhanced intrinsic AMPK signaling and promoted mitochondrial respiration with increased basal oxygen consumption rates (OCR), higher maximal OCR, and augmented spare respiratory capacity. These changes were accompanied by increased mitochondrial density and elevated expression of proteins involved in mitochondrial fusion. AMPKγ2-transduction also increased T cell glycolytic activity. This combination of metabolic reprogramming enhanced in vitro T cell expansion while promoting memory T cell yield. Finally, when activated under decreasing glucose conditions, AMPKγ2-transduced T cells maintained higher levels of both proliferation and inflammatory cytokine production. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPKγ2 can improve the expansion and function of human T cells for subsequent use in adoptive cellular therapies.Key pointsLentiviral Transduction of AMPKγ2 increases oxidative metabolism in human T cellsAMPKγ2 transduction enhances in vitro proliferation without inducing exhaustionAMPKγ2-transduced T cells function better under low glucose conditions |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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