{"doi":"10.1172/jci165723","title":"Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity","abstract":"STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling-mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.","journal":"Journal of Clinical Investigation","year":2023,"id":357925,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"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":524227,"name":"Xiaoqi Wang","orcid":"0000-0001-8251-9102","position":1,"is_corresponding":false},{"id":474659,"name":"Qingxiao Song","orcid":"0000-0001-9243-5666","position":2,"is_corresponding":false},{"id":474658,"name":"Shijie Yang","orcid":"0000-0003-3452-3638","position":3,"is_corresponding":false},{"id":108571,"name":"Xiwei Wu","orcid":"0000-0002-7071-1671","position":4,"is_corresponding":false},{"id":318404,"name":"Dongyun Yang","orcid":"0000-0003-0736-4977","position":5,"is_corresponding":false},{"id":686467,"name":"Isabelle Marié","orcid":"0000-0002-3091-7624","position":6,"is_corresponding":false},{"id":108565,"name":"Hanjun Qin","orcid":"0000-0002-0370-0913","position":7,"is_corresponding":false},{"id":1038614,"name":"Moqian Zheng","orcid":null,"position":8,"is_corresponding":false},{"id":475918,"name":"Ubaydah Nasri","orcid":null,"position":9,"is_corresponding":false},{"id":474656,"name":"Xiaohui Kong","orcid":"0000-0002-8353-3288","position":10,"is_corresponding":false},{"id":474657,"name":"Bixin Wang","orcid":"0009-0000-9613-2734","position":11,"is_corresponding":false},{"id":1108044,"name":"Elizabeth Lizhar","orcid":null,"position":12,"is_corresponding":false},{"id":878692,"name":"Kaniel Cassady","orcid":"0000-0001-8949-3507","position":13,"is_corresponding":false},{"id":1108045,"name":"Josh Tompkins","orcid":null,"position":14,"is_corresponding":false},{"id":479427,"name":"David E. Levy","orcid":"0000-0002-7320-7788","position":15,"is_corresponding":false},{"id":236735,"name":"Paul J. Martin","orcid":"0000-0001-9051-1215","position":16,"is_corresponding":false},{"id":506457,"name":"Xi Zhang","orcid":"0000-0002-8548-2832","position":17,"is_corresponding":false},{"id":474662,"name":"Defu Zeng","orcid":"0000-0001-9585-1411","position":18,"is_corresponding":false},{"id":1107731,"name":"Qinjian Li","orcid":"0000-0002-6496-8067","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:13:39.186262Z","pmid":"37526084","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":[]}