{"doi":"10.1101/2025.10.06.680655","title":"Pre-division TCF1 drop determines long-term CD8 T cell fates","abstract":"T Cell Factor 1 (TCF1) is a master transcription factor controlling T cell development and peripheral T cell differentiation during infection, cancer, and autoimmunity. TCF1 is highly expressed in naive CD8 T cells but must be downregulated as T cells proliferate to become effectors. If and how TCF1 plays a role during T cell priming prior to cell cycle entry is unknown. Surprisingly, we found that TCF1 expression is rapidly downregulated within hours after antigen encounter in both murine and human CD8 T cells, even before T cells enter cell cycle. TCF1 then rebounds to high levels upon cell cycle entry, ultimately declining again with proliferation and effector differentiation. This rapid pre-division drop and rebound occurs in diverse settings, including infection and cancer. The magnitude of the pre-division TCF1 drop is modulated by TCR signal strength and inflammatory cytokines and strikingly, regulates long-term effector and memory fates. Paired transcriptomic and epigenetic analyses revealed that TCF1-regulated chromatin regions were remodeled within hours following antigen encounter, activating effector and inflammatory cytokine signaling modules and poising T cells for effector differentiation. Remarkably, transient siRNA-mediated TCF1 downmodulation during the pre-division priming phase was sufficient to induce long-term population effector skewing. We have uncovered a novel mechanism whereby pre-division dynamic TCF1 regulation determines long-term CD8 T cell fate commitment, potentially serving as a critical checkpoint regulating T cell responses in infection, cancer, and autoimmunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577026,"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":0.9525,"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":765988,"name":"Maider Astorkia","orcid":"0000-0001-5572-8830","position":1,"is_corresponding":false},{"id":298984,"name":"Melissa M. Wolf","orcid":"0000-0003-2038-6978","position":2,"is_corresponding":false},{"id":1006947,"name":"Michael Rudloff","orcid":"0000-0002-2950-1218","position":3,"is_corresponding":false},{"id":1485284,"name":"Claudia N. McDavid","orcid":null,"position":4,"is_corresponding":false},{"id":419732,"name":"Megan M. Erwin","orcid":"0000-0002-7014-0856","position":5,"is_corresponding":false},{"id":1018126,"name":"Kristen A. Murray","orcid":"0009-0002-7772-3277","position":6,"is_corresponding":false},{"id":1006948,"name":"Jessica J. Roetman","orcid":"0009-0005-7783-8308","position":7,"is_corresponding":false},{"id":1018125,"name":"Carlos R. Detrés Román","orcid":"0009-0008-1223-4177","position":8,"is_corresponding":false},{"id":1485285,"name":"Zachary D. Ewell","orcid":null,"position":9,"is_corresponding":false},{"id":1485283,"name":"Lincoln A. Brown","orcid":null,"position":10,"is_corresponding":false},{"id":33390,"name":"W. Murray","orcid":null,"position":11,"is_corresponding":false},{"id":237940,"name":"Paul Zumbo","orcid":"0000-0001-7234-2024","position":12,"is_corresponding":false},{"id":53879,"name":"Doron Betel","orcid":"0000-0002-8006-7752","position":13,"is_corresponding":false},{"id":627822,"name":"Mary Philip","orcid":"0000-0001-7496-2630","position":14,"is_corresponding":false},{"id":927657,"name":"Natalie R. Favret","orcid":"0000-0002-4458-7785","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41279579","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":[]}