{"doi":"10.1101/2023.06.12.544686","title":"AMPK Drives Both Glycolytic and Oxidative Metabolism in T Cells During Graft-versus-host Disease","abstract":"ABSTRACT Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process reliant on the cellular energy sensor AMP-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia (GVL) effects. In the current studies, murine T cells lacking AMPK decreased oxidative metabolism at early timepoints post-transplant and were also unable to mediate a compensatory increase in glycolysis following inhibition of the electron transport chain. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and following expansion in vivo in a modified model of GVHD. Immunoprecipitation of proteins from day 7 allogeneic T cells, using an antibody specific to phosphorylated AMPK targets, recovered lower levels of multiple glycolysis-related proteins including the glycolytic enzymes aldolase, enolase, pyruvate kinase M (PKM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Functionally, murine T cells lacking AMPK exhibited impaired aldolase activity following anti-CD3/CD28 stimulation and a decrease in GAPDH activity on day 7 post-transplant. Importantly, these changes in glycolysis correlated with an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma (IFNγ) upon antigenic re-stimulation. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells during GVHD and endorse further study of AMPK inhibition as a potential target for future clinical therapies. KEY POINTS AMPK plays a key role in driving both and oxidative and glycolytic metabolism in T cells during graft-versus-host disease (GVHD) Absence of AMPK simultaneously impairs both glycolytic enzyme activity, most notably by aldolase, and interferon gamma (IFNγ) production","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":408539,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1110914,"name":"Erica Braverman","orcid":"0000-0002-5072-5291","position":1,"is_corresponding":false},{"id":559235,"name":"Lee-Kai Sun","orcid":"0000-0002-2441-8407","position":2,"is_corresponding":false},{"id":760937,"name":"Darlene Monlish","orcid":"0000-0003-3374-9117","position":3,"is_corresponding":false},{"id":1110917,"name":"Christopher Wittmann","orcid":"0000-0002-8450-7671","position":4,"is_corresponding":false},{"id":735490,"name":"Manda Ramsey","orcid":null,"position":5,"is_corresponding":false},{"id":1188187,"name":"Richard Caitley","orcid":null,"position":6,"is_corresponding":false},{"id":237072,"name":"William F. Hawse","orcid":"0000-0001-8371-3345","position":7,"is_corresponding":false},{"id":475624,"name":"Craig A. Byersdorfer","orcid":"0000-0002-0030-3699","position":8,"is_corresponding":false},{"id":1110918,"name":"Archana Ramgopal","orcid":"0000-0002-5172-723X","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:21:18.414003Z","pmid":"37398326","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}