Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function

• Published in: The Journal of biological chemistry 2024-01, Vol.300 (1), p.105488, Article 105488
• Main Authors: Braverman, Erica L, McQuaid, Margaret A, Schuler, Herbert, Qin, Mengtao, Hani, Sophia, Hippen, Keli, Monlish, Darlene A, Dobbs, Andrea K, Ramsey, Manda J, Kemp, Felicia, Wittmann, Christopher, Ramgopal, Archana, Brown, Harrison, Blazar, Bruce, Byersdorfer, Craig A
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; CD4-Positive T-Lymphocytes - enzymology; Cells, Cultured; Cytokines - metabolism; Gene Expression - genetics; Glucose - metabolism; Humans; Memory T Cells - enzymology; Mitochondria - metabolism; Signal Transduction; T-Lymphocytes - cytology; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; Th2 Cells - metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2023.105488

Cellular therapies are currently employed to treat a variety of disease processes. For T cell-based therapies, success often relies on the metabolic fitness of the T cell product, where cells with enhanced metabolic capacity demonstrate improved in vivo efficacy. AMP-activated protein kinase (AMPK) is a cellular energy sensor which combines environmental signals with cellular energy status to enforce efficient and flexible metabolic programming. 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, higher maximal oxygen consumption rate, and augmented spare respiratory capacity. These changes were accompanied by increased proliferation and inflammatory cytokine production, particularly within restricted glucose environments. Introduction of AMPKγ2 into bulk CD4 T cells decreased RNA expression of canonical Th2 genes, including the cytokines interleukin (IL)-4 and IL-5, while introduction of AMPKγ2 into individual Th subsets universally favored proinflammatory cytokine production and a downregulation of IL-4 production in Th2 cells. When AMPKγ2 was overexpressed in regulatory T cells, both in vitro proliferation and suppressive capacity increased. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPKγ2 can improve the expansion and functional potential of human T cells for use in a variety of adoptive cellular therapies.