{"doi":"10.1111/acel.70109","title":"Aging Compromises Terminal Differentiation Program of Cytotoxic Effector Lineage and Promotes Exhaustion in <scp>CD8</scp><sup>+</sup> T Cells Responding to Coronavirus Infection","abstract":"ABSTRACT T cell aging increases the risk of viral infection‐related morbidity and mortality and reduces vaccine efficacy in the elderly. A major hallmark of T cell aging is the loss of quiescence and shift toward terminal differentiation during homeostasis. However, how aging impacts the differentiation program of virus‐specific T cells during infection is unclear. Here, in a murine coronavirus (MHV) infection model with age‐associated increased mortality, we demonstrate that aging impairs, instead of promoting, the terminal differentiation program of virus‐specific CD8 + T cells. Upon infection, CD8 + and CD4 + T cells in old mice showed marked reduction in clonal expansion and upregulation of immune checkpoints associated with T cell exhaustion. Bulk and single‐cell transcriptomics showed that aging upregulated the T cell exhaustion transcriptional program associated with TOX in virus‐specific CD8 + T cells and shifted the myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, aging downregulated the transcriptional program of terminally differentiated effector CD8 + T cells and diminished the CX3CR1 + cytotoxic effector lineage. Mechanistically, virus‐specific CD8 + T cells from infected aged mice displayed defects in inducing transcription factors ZEB2 and KLF2, which were required for terminal differentiation of effector CD8 + T cells. Together, our study shows that aging impairs terminal differentiation and promotes exhaustion of virus‐specific CD8 + T cells responding to coronavirus infection through dysregulating expression of lineage‐defining transcription factors.","journal":"Aging Cell","year":2025,"id":521237,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"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":623475,"name":"Guohua Lou","orcid":"0000-0002-2829-3429","position":1,"is_corresponding":false},{"id":1025504,"name":"Ying Luo","orcid":"0000-0002-1325-2296","position":2,"is_corresponding":false},{"id":1025505,"name":"Kiddist Yihunie","orcid":"0000-0002-0863-4863","position":3,"is_corresponding":false},{"id":1221381,"name":"Jonathan Hoar","orcid":"0009-0004-7584-4141","position":4,"is_corresponding":false},{"id":4375,"name":"J. Daniel","orcid":"0000-0002-2957-4687","position":5,"is_corresponding":false},{"id":285068,"name":"Bret M. Evers","orcid":"0000-0001-5686-0315","position":6,"is_corresponding":false},{"id":39928,"name":"Chen Yao","orcid":"0000-0001-6852-5661","position":7,"is_corresponding":false},{"id":623483,"name":"Tuoqi Wu","orcid":"0000-0002-4003-1034","position":8,"is_corresponding":false},{"id":484320,"name":"Ziang Zhu","orcid":"0009-0008-4231-7213","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40396260","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":[]}