{"doi":"10.1093/jimmun/vkaf283.945","title":"Interactions between the T cell receptor and its cognate epitope determine memory CD8+ T cell functional fates 3107","abstract":"Abstract Description Effective CD8+ T cell priming requires T cell receptor (TCR) recognition of cognate antigen, costimulation, and inflammatory signals, which leads to clonal expansion, potent effector functions, and memory CD8+ T (TM) cells. While stronger cognate antigen signals drive larger primary effector and memory pools, the current dogma is that changes to TCR stimulation do not affect CD8+ TM cell functions. We used transgenic TCR mouse models, flow cytometry, epigenetic profiling, and adoptive T cell transfers to investigate if modulating TCR interactions with its cognate antigen impacts the phenotypic and functional characteristics of CD8+ TM cells. By mutating specific residues in model epitopes, we reveal that altering TCR interactions with its cognate epitope, but not decreasing TCR signaling strength, changes the fates of CD8+ TM cells. These cells demonstrated increased expression of central/stem cell TM cell (TCM/TSCM) markers (e.g., CD62L, EOMES, BCL2), enhanced chromatin accessibility in stemness-related genes (e.g., Lef1, Bcl6), and superior functions such as greater ability to re-expand, generate diverse progeny, and clear pathogens. Our findings show TCR signaling is a major driver of CD8+ T cell differentiation and dictates TM cell functional programming. This work challenges the notion that stronger epitopes are the most effective in inducing long-lasting TM cells, potentially reshaping our thinking of epitope selection for vaccine design and adoptive T cell therapies. Funding Sources Supported by NIH T32GM7288 and NIH/NIAID F31AI172421 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)","journal":"The Journal of Immunology","year":2025,"id":582634,"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":0.9504,"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":1495015,"name":"S. Chin","orcid":null,"position":1,"is_corresponding":false},{"id":1166202,"name":"Prithviraj Nandigrami","orcid":"0000-0002-2269-9292","position":2,"is_corresponding":false},{"id":86519,"name":"Christopher B. McClain","orcid":"0000-0002-8246-4639","position":3,"is_corresponding":false},{"id":723217,"name":"András Fiser","orcid":"0000-0003-0085-5335","position":4,"is_corresponding":false},{"id":653328,"name":"Grégoire Lauvau","orcid":"0000-0002-3050-2664","position":5,"is_corresponding":false},{"id":745191,"name":"Erik Guillen","orcid":"0000-0001-7873-829X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":null,"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":[]}