{"doi":"10.1101/2025.07.18.663399","title":"Constraints and tunability of antigen-agnostic memory durability","abstract":"Apart from antigen-specific immune memory, infection or vaccination can also induce antigen-agnostic memory including bystander T cell activation memory and trained innate immunity. Determinants of the durability of such memory remain unclear. We developed mathematical models to show that antigen-agnostic memory durability is constrained by immune cell turnover and cytokine dependence. Trained immunity durability is further constrained by the fidelity of epigenetic state transmission during self-renewal and differentiation. Using computer simulations and a machine learning-based parameter-phenotype mapping approach, we find that positive feedback mediated by immune cell-secreted cytokines, a motif seen across immune circuits, can lead to tunable memory involving excitable responses to acute challenges followed by slow relaxation to the pre-challenge baseline. We propose specific experiments to test predictions from our models. Our findings thus reveal a cell extrinsic mechanism that can overcome the constraints imposed by cell turnover and epigenetic state transmission to drive long-lasting, tunable antigen-agnostic memory.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558530,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"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":1208268,"name":"Can Liu","orcid":"0000-0001-5521-3335","position":1,"is_corresponding":false},{"id":620705,"name":"William W. Lau","orcid":"0000-0003-0190-3722","position":2,"is_corresponding":false},{"id":95756,"name":"Rachel Sparks","orcid":"0000-0001-8216-5084","position":3,"is_corresponding":false},{"id":78353,"name":"John S. Tsang","orcid":"0000-0003-3186-3047","position":4,"is_corresponding":false},{"id":267403,"name":"Shubham Tripathi","orcid":"0000-0002-0141-987X","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40791445","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":[]}