{"doi":"10.1172/jci.insight.181568","title":"The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses","abstract":"In allogeneic hematopoietic transplantation, donor αβ T cells attack recipient tissues, causing graft versus host disease (GVHD). A longstanding question has been how GVHD is maintained despite T cell exhaustion from chronic alloantigen stimulation. In other exhaustion models, CD8 responses are sustained by CD39loTim-3loToxhiTCF-1hi precursor exhausted T cells (TPEX). Here we characterize CD8+ TPEX in the B6(H-2b)→129(H-2b) GVHD model wherein responses against the minor histocompatibility antigen H60 can be tracked using MHCI-tetramers (TetH60). Early after transplant, TetH60+ CD8 cells were uniformly PD-1hiToxhi, whereas TetH60- cells also had PD-1loToxlo cells, indicative of more diverse antigen experiences. Among TetH60+ and TetH60- populations were CD39loTCF-1hi cells. Upon competitive retransplantation, TetH60+CD39loTCF-1hi cells outcompeted TetH60+CD39hiTCF-1lo cells and underwent self-renewal, whereas CD39hiTCF-1lo cells did not yield TCF-1hi cells. To test the role of TCF-1, we studied CD8 cells lacking long TCF-1 isoforms (p45-/-). P45-/- cells were outcompeted by WT cells when transplanted into 129 recipients, though they expanded similarly in syngeneic recipients. In the B6→C3H.SW(H-2b) model, p45-/- CD8 cells caused less weight loss than did WT CD8 cells; however, histopathologic GVHD was similar in both groups. P45-/- and WT CD8 cells also had similar graft versus leukemia activity. These results highlight the complex biology of TCF-1 in supporting alloreactive T cell function.","journal":"JCI Insight","year":2025,"id":527106,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":640326,"name":"Faruk Sacirbegovic","orcid":"0000-0001-5686-7760","position":1,"is_corresponding":false},{"id":472307,"name":"Sarah Rosenberger","orcid":null,"position":2,"is_corresponding":false},{"id":1403761,"name":"Emily R McFerran","orcid":null,"position":3,"is_corresponding":false},{"id":1403762,"name":"Kentin C Codispot","orcid":null,"position":4,"is_corresponding":false},{"id":1403763,"name":"Laura Garcia-Dieguez","orcid":null,"position":5,"is_corresponding":false},{"id":1403249,"name":"Alexander M. Rowe","orcid":"0000-0001-7265-6437","position":6,"is_corresponding":false},{"id":1135514,"name":"Wenzhong Wei","orcid":null,"position":7,"is_corresponding":false},{"id":326891,"name":"Dhanpat Jain","orcid":"0000-0003-3845-0798","position":8,"is_corresponding":false},{"id":519526,"name":"Jennifer M. McNiff","orcid":"0000-0001-8142-6481","position":9,"is_corresponding":false},{"id":548429,"name":"Warren D. Shlomchik","orcid":"0000-0002-0430-9078","position":10,"is_corresponding":false},{"id":1199658,"name":"Kevin Quann","orcid":"0000-0003-2213-3771","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:50:34.851930Z","pmid":"41059570","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":[]}