AMPK drives both glycolytic and oxidative metabolism in murine and human T cells during graft-versus-host disease.

Autor:	Ramgopal A; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Braverman EL; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Sun LK; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Monlish D; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Wittmann C; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Kemp F; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Qin M; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA.; School of Medicine, Tsinghua University, Beijing, China., Ramsey MJ; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA., Cattley R; Department of Immunology, University of Pittsburgh, Pittsburgh, PA., Hawse W; Department of Immunology, University of Pittsburgh, Pittsburgh, PA., Byersdorfer CA; Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh PA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Aug 13; Vol. 8 (15), pp. 4149-4162.
DOI:	10.1182/bloodadvances.2023010740
Abstrakt:	Abstract: Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process involving the cellular energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia effects. In the current studies, murine AMPK knock-out (KO) T cells decreased oxidative metabolism at early time points posttransplant and lacked a compensatory increase in glycolysis after inhibition of the electron transport chain. Immunoprecipitation using an antibody specific to phosphorylated targets of AMPK determined that AMPK modified interactions of several glycolytic enzymes including aldolase, enolase, pyruvate kinase M, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), with enzyme assays confirming impaired aldolase and GAPDH activity in AMPK KO T cells. Importantly, these changes in glycolysis correlated with both an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma upon antigenic restimulation and a decrease in the total number of donor CD4 T cells recovered at later times posttransplant. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and after expansion in vivo. Xenogeneic GVHD results also mirrored those of the murine model, with reduced CD4/CD8 ratios and a significant improvement in disease severity. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells and endorse further study of AMPK inhibition as a potential clinical target for future GVHD therapies. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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