{"doi":"10.1172/jci178089","title":"A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection","abstract":"Sustained CD4+ T cell immunity is required for resolution of acute hepatitis C virus (HCV) infection, but the response remains poorly characterized. Here, circulating CD4+ T cells with high programmed cell death 1 (PD-1) and ICOS coexpression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees. Coproduction of T follicular helper (Tfh) (IL-21 and CXCL13) and Th1 (IFN-γ and TNF) cytokines after stimulation with HCV nonstructural proteins demonstrated that the response was predominately Tfh1 like and virus specific. Transcriptional analysis verified a Tfh1 lineage assignment. Effector-related genes such as ADGRG1 (GPR56), ZNF683 (Hobit), and KLRB1 (CD161) were also expressed. HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication. Most circulating and intrahepatic PD-1hiICOShi CD4+ Tfh1-like cells did not express CXCR5 and therefore resembled CXCR5-CXCL13+ peripheral helper cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1hiICOShi CD4+ Tfh1-like cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks compared with HCV infection. The PD-1hiICOShi phenotype and temporal association between the peak response and alanine aminotransferase may provide markers to guide human studies of CD4+ T cell immunity against HCV and other hepatotropic viruses.","journal":"Journal of Clinical Investigation","year":2025,"id":546908,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"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":713805,"name":"William G. Bremer","orcid":null,"position":1,"is_corresponding":false},{"id":497428,"name":"Christopher C. Phelps","orcid":"0000-0003-4545-5650","position":2,"is_corresponding":false},{"id":742271,"name":"Yan Zhou","orcid":"0000-0003-4793-7303","position":3,"is_corresponding":false},{"id":585332,"name":"David G. Bowen","orcid":"0000-0002-7965-5581","position":4,"is_corresponding":false},{"id":728896,"name":"Zhaohui Xu","orcid":"0000-0003-0645-1737","position":5,"is_corresponding":false},{"id":418558,"name":"Robert E. Lanford","orcid":"0000-0003-4980-2920","position":6,"is_corresponding":false},{"id":636807,"name":"Naglaa H. Shoukry","orcid":"0000-0002-8817-8238","position":7,"is_corresponding":false},{"id":227332,"name":"Arash Grakoui","orcid":"0000-0002-6002-7518","position":8,"is_corresponding":false},{"id":515269,"name":"Nicole Skinner","orcid":"0000-0003-4807-022X","position":9,"is_corresponding":false},{"id":548533,"name":"Christopher M. Walker","orcid":"0000-0003-1580-1620","position":10,"is_corresponding":false},{"id":713402,"name":"Heather Blasczyk","orcid":"0000-0002-0485-3591","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40956619","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":[]}