{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:10:16Z","timestamp":1783923016524,"version":"3.55.0"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 841 A6, grant number 80750187, CRC 1648\/1 2024, grant number 512741711, CRC 1328, grant number 335447717"],"award-info":[{"award-number":["CRC 841 A6, grant number 80750187, CRC 1648\/1 2024, grant number 512741711, CRC 1328, grant number 335447717"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009139","name":"Deutsches Zentrum f\u00fcr Infektionsforschung","doi-asserted-by":"publisher","award":["grant number TTU 04.820"],"award-info":[{"award-number":["grant number TTU 04.820"]}],"id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hepatitis C virus (HCV) infection frequently progresses to chronicity, where persistent antigen exposure drives differentiation of virus-specific CD8+ T cells toward an exhausted phenotype. This state is defined by progressive upregulation of inhibitory receptors and functional impairment of antigen-specific T cells. Because patients span distinct clinical stages from acute infection to spontaneous resolution or therapy induced sustained virological response, HCV provides a unique model to study how T-cell exhaustion is established, maintained, and potentially reversed. While PD1 and TIGIT are well established in this context, CD96 (TACTILE) is a less-characterized receptor that shares its ligand CD155 with TIGIT and DNAM-1 and may modulate CD8+ T-cell differentiation and function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To evaluate the role of CD96 across infection stages, we used HCV-specific MHC class I tetramers combined with high-dimensional flow cytometry to phenotypically profile virus-specific CD8+ T-cells\n                      <jats:italic>ex vivo<\/jats:italic>\n                      in 32 patients spanning acute, subacute, chronic, spontaneously resolved infection, and post-treatment sustained virological response. We assessed CD96 co-expression with PD1\/TIGIT, transcription factors (TCF1, TOX, IRF4, T-bet, NR2F6), and relevant differentiation and exhaustion markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CD96+ HCV-specific CD8+ T cells consistently increased relative to bulk across all stages of HCV infection, with approximately four-fold higher frequencies than bulk CD96+ CD8+ T cells (p&amp;lt;0.0001), and highest frequencies of 51,13% observed in the chronic group. Because CD96 expression was predominantly distributed continuously rather than strictly bimodal, we also report CD96 MFI as a continuous measurement alongside CD96+ frequencies. Phenotypically, HCV-specific and bulk CD96+ CD8+ T cells were enriched for IRF4+, TOX+ and TCF1+ subsets, suggesting possible reduced effector features and increased memory-associated characteristics. Notably, the CD96+ PD1+ TIGIT+ subset was about five times higher in HCV-specific than in bulk CD8+ T-cell populations (p&amp;lt;0.0001). In cross-sectional comparison, frequencies of CD96+ PD1+ TIGIT+ HCV-specific CD8+ T cells decreased, while the CD96- PD1- TIGIT- counterparts expanded.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify CD96 as a marker of a phenotypically distinct checkpoint-associated HCV-specific CD8+ T-cell subset featuring memory-associated rather than terminally exhausted states. Whether this phenotypic association has functional or therapeutic significance for combination immune therapy will require future studies, including direct functional assays of sorted CD96+ versus CD96- HCV-specific CD8+ T cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1883007","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:33:38Z","timestamp":1783920818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD96 marks a phenotypically distinct checkpoint-associated HCV-specific CD8+ T-cell subset featuring memory-associated states"],"prefix":"10.3389","volume":"17","author":[{"given":"Maximilian","family":"Knapp","sequence":"first","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine","place":["Cologne, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Ackermann","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Institute of Hematopathology Hamburg HpH","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Wittner","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]},{"name":"PROVIREX Genome Editing Therapies GmbH","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Beisel","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Department of Internal Medicine IV & Division of Infectious Disease and Tropical Medicine, University Hospital Heidelberg","place":["Heidelberg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Cords","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Westphal","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liz","family":"Lam","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Kummer","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Woost","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Peine","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Pischke","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schulthei\u00df","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University Hospital Basel","place":["Basel, Switzerland"]},{"name":"Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar W.","family":"Lohse","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]},{"name":"European Reference Network for Hepatological Diseases (ERN RARE-LIVER)","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Walker","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-Universit\u00e4t","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Timm","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-Universit\u00e4t","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mascha","family":"Binder","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University Hospital Basel","place":["Basel, Switzerland"]},{"name":"Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Schulze zur Wiesch","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"German Center for Infection Research (DZIF), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","article-title":"Hepatitis C","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s2468-1253(25)00375-9","article-title":"The burden of chronic hepatitis B and C in 2022 and progress towards elimination: a global report","author":"Cui","year":"2026","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/j.1365-2893.2005.00651.x","article-title":"Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies","volume":"13","author":"Micallef","year":"2006","journal-title":"J Viral Hepat"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15827","article-title":"Efficacy and safety of DAA in children and adolescents with chronic HCV infection: a systematic review and meta-analysis","volume":"44","author":"Indolfi","year":"2024","journal-title":"Liver Int"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/v14061325","article-title":"Direct-acting antiviral agents for hepatitis C virus infection-from drug discovery to successful implementation in clinical practice","volume":"14","author":"Dietz","year":"2022","journal-title":"Viruses"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/tmi.13450","article-title":"Achieving a high cure rate with direct-acting antivirals for chronic hepatitis C virus infection in Cameroon: a multi-clinic demonstration project","volume":"25","author":"Coyer","year":"2020","journal-title":"Trop Med Int Health"},{"key":"B7","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/b978-0-12-385032-4.00002-1","article-title":"Adaptive immunity to the hepatitis C virus","volume":"78","author":"Walker","year":"2010","journal-title":"Adv Virus Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318","article-title":"CD8 T cell exhaustion during chronic viral infection and cancer","volume":"37","author":"McLane","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1146\/annurev-immunol-090222-110914","article-title":"T cell exhaustion","volume":"42","author":"Baessler","year":"2024","journal-title":"Annu Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00689-z","article-title":"Clinical implications of T cell exhaustion for cancer immunotherapy","volume":"19","author":"Chow","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00409-07","article-title":"Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction","volume":"81","author":"Golden-Mason","year":"2007","journal-title":"J Virol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00376-11","article-title":"High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome","volume":"82","author":"Kasprowicz","year":"2008","journal-title":"J Virol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/jci126277","article-title":"Hepatitis C virus-specific CD4+ T cell phenotype and function in different infection outcomes","volume":"130","author":"Chen","year":"2020","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation","volume":"182","author":"Krummel","year":"1995","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000313","article-title":"Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1\/CTLA-4 blockade","volume":"5","author":"Nakamoto","year":"2009","journal-title":"PloS Pathog"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00345-8","article-title":"The foundations of immune checkpoint blockade and the ipilimumab approval decennial","volume":"21","author":"Korman","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"B19","doi-asserted-by":"publisher","first-page":"10781552251324896","DOI":"10.1177\/10781552251324896","article-title":"Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer","author":"Ali","year":"2025","journal-title":"J Oncol Pharm Pract"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29050247","article-title":"Immune checkpoint inhibitors in cancer therapy","volume":"29","author":"Shiravand","year":"2022","journal-title":"Curr Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.148.8.2600","article-title":"Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily","volume":"148","author":"Wang","year":"1992","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4161\/21624011.2014.953410","article-title":"Stress-related and homeostatic cytokines regulate V\u03b39V\u03b42 T-cell surveillance of mevalonate metabolism","volume":"3","author":"Gruenbacher","year":"2014","journal-title":"Oncoimmunology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adx7485","article-title":"HIV-1 manipulates CD96 on CD4(+) T cells to subvert antiviral immunity","volume":"11","author":"Dehn","year":"2025","journal-title":"Sci Adv"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12205","article-title":"The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor-infiltrating T cells","volume":"97","author":"Lepletier","year":"2019","journal-title":"Immunol Cell Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1107\/s2053273319094658","article-title":"Structural basis for CD96 immune receptor recognition of nectin-like protein-5, CD155","volume":"27","author":"Deuss","year":"2019","journal-title":"Structure"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m807698200","article-title":"CD96 interaction with CD155 via its first Ig-like domain is modulated by alternative splicing or mutations in distal Ig-like domains","volume":"284","author":"Meyer","year":"2009","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.10.102","article-title":"The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1","volume":"364","author":"Seth","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212443","article-title":"Interaction between nectin-1 and the human natural killer cell receptor CD96","volume":"14","author":"Holmes","year":"2019","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2850","article-title":"The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions","volume":"15","author":"Chan","year":"2014","journal-title":"Nat Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"10624","DOI":"10.1038\/s41598-019-47024-8","article-title":"HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules","volume":"9","author":"Ackermann","year":"2019","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.ra119.009261","article-title":"Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1","volume":"294","author":"Deuss","year":"2019","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2019.01.007","article-title":"How natural killer cell receptors stick to cell-cell adhesion proteins","volume":"27","author":"Karade","year":"2019","journal-title":"Structure"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030788","article-title":"Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule","volume":"198","author":"Bottino","year":"2003","journal-title":"J Exp Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxh059","article-title":"Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2\/CD112)","volume":"16","author":"Tahara-Hanaoka","year":"2004","journal-title":"Int Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-016-1799-4","article-title":"Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155","volume":"65","author":"Zhang","year":"2016","journal-title":"Cancer Immunol Immunother"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/cells12020309","article-title":"An inhibitory role for human CD96 endodomain in T cell anti-tumor responses","volume":"12","author":"Wang","year":"2023","journal-title":"Cells"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.cir-18-0637","article-title":"CD96 is an immune checkpoint that regulates CD8(+) T-cell antitumor function","volume":"7","author":"Mittal","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1445949","article-title":"Deficiency of host CD96 and PD-1 or TIGIT enhances tumor immunity without significantly compromising immune homeostasis","volume":"7","author":"Harjunp\u00e4\u00e4","year":"2018","journal-title":"Oncoimmunology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202204951","article-title":"Single-cell landscape highlights heterogenous microenvironment, novel immune reaction patterns, potential biomarkers and unique therapeutic strategies of cervical squamous carcinoma, human papillomavirus-associated (HPVA) and non-HPVA adenocarcinoma","volume":"10","author":"Qiu","year":"2023","journal-title":"Adv Sci (Weinh)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3892\/mco.2020.2171","article-title":"An obstructive role of NK cells on metastatic growth of clear-cell sarcoma cells in a xenoplant murine model","volume":"14","author":"Hanamatsu","year":"2021","journal-title":"Mol Clin Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10092146","article-title":"Evaluating antibody pharmacokinetics as prerequisite for determining true efficacy as shown by dual targeting of PD-1 and CD96","volume":"10","author":"Boch","year":"2022","journal-title":"Biomedicines"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003667","article-title":"Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer","volume":"10","author":"Wang","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00538-y","article-title":"Direct interaction between CD155 and CD96 promotes immunosuppression in lung adenocarcinoma","volume":"18","author":"Zhang","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.am2024-3915","article-title":"Abstract 3915: BMS-986442 (AGEN1777), a novel TIGIT\/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models","volume":"84","author":"Ward","year":"2024","journal-title":"Cancer Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/978-1-0716-4414-0_14","article-title":"Utilizing pMHC multimers to study antigen-specific T cells and T cell exhaustion in chronic viral infections","volume":"2904","author":"Keetz","year":"2025","journal-title":"Methods Mol Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-251124","article-title":"Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies","volume":"115","author":"Alanio","year":"2010","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200424898","article-title":"Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells","volume":"34","author":"Barnes","year":"2004","journal-title":"Eur J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(12)70010-5","article-title":"Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine","volume":"12","author":"Grebely","year":"2012","journal-title":"Lancet Infect Dis"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.886646","article-title":"Transcriptional pattern analysis of virus-specific CD8+ T cells in hepatitis C infection: increased expression of TOX and eomesodermin during and after persistent antigen recognition","volume":"13","author":"Wildner","year":"2022","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01590-14","article-title":"Impact of sequence variation in a dominant HLA-A*02-restricted epitope in hepatitis C virus on priming and cross-reactivity of CD8+ T cells","volume":"88","author":"Ziegler","year":"2014","journal-title":"J Virol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2015.07.008","article-title":"Natural prevalence of resistance-associated variants in hepatitis C virus NS5A in genotype 3a-infected people who inject drugs in Germany","volume":"70","author":"Walker","year":"2015","journal-title":"J Clin Virol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2017.04.008","article-title":"A genotype independent, full-genome reverse-transcription protocol for HCV genotyping and resistance testing","volume":"91","author":"Walker","year":"2017","journal-title":"J Clin Virol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/jci200318509","article-title":"Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers","volume":"112","author":"Day","year":"2003","journal-title":"J Clin Invest"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8215","article-title":"High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection","volume":"181","author":"Rutebemberwa","year":"2008","journal-title":"J Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.5129","article-title":"Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C","volume":"15","author":"Larrubia","year":"2009","journal-title":"World J Gastroenterol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422x-7-310","article-title":"PD-1 expression on peripheral CD8+ TEM\/TEMRA subsets closely correlated with HCV viral load in chronic hepatitis C patients","volume":"7","author":"Shen","year":"2010","journal-title":"Virol J"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02021-06","article-title":"Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression","volume":"81","author":"Radziewicz","year":"2007","journal-title":"J Virol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1312772110","article-title":"Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)","volume":"110","author":"Fuller","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2014.10.018","article-title":"The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function","volume":"26","author":"Johnston","year":"2014","journal-title":"Cancer Cell"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.15730","article-title":"CD155\/TIGIT signaling regulates the effector function of tumor-infiltrating CD8+ T cell by NF-\u03baB pathway in colorectal cancer","volume":"37","author":"Li","year":"2022","journal-title":"J Gastroenterol Hepatol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1097\/cji.0000000000000330","article-title":"TIGIT can exert immunosuppressive effects on CD8+ T cells by the CD155\/TIGIT signaling pathway for hepatocellular carcinoma in vitro","volume":"43","author":"Zhang","year":"2020","journal-title":"J Immunother"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/35005534","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.7.4686","article-title":"Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor alpha and CD62L","volume":"175","author":"Bachmann","year":"2005","journal-title":"J Immunol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","article-title":"Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms","volume":"52","author":"Beltra","year":"2020","journal-title":"Immunity"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17232","article-title":"PD1 signal transduction pathways in T cells","volume":"8","author":"Arasanz","year":"2017","journal-title":"Oncotarget"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-012017-043208","article-title":"CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions","volume":"69","author":"Hashimoto","year":"2018","journal-title":"Annu Rev Med"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07121-9","article-title":"Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells","volume":"627","author":"Guan","year":"2024","journal-title":"Nature"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.02.012","article-title":"Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses","volume":"40","author":"Joller","year":"2014","journal-title":"Immunity"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining 'T cell exhaustion'","volume":"19","author":"Blank","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"2","DOI":"10.5483\/bmbrep.2021.54.1.229","article-title":"Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy","volume":"54","author":"Jin","year":"2021","journal-title":"BMB Rep"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12518","article-title":"TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy","volume":"276","author":"Dougall","year":"2017","journal-title":"Immunol Rev"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-15-0944","article-title":"Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy","volume":"6","author":"Blake","year":"2016","journal-title":"Cancer Discov"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003081","article-title":"Cutting edge: TIGIT has T cell-intrinsic inhibitory functions","volume":"186","author":"Joller","year":"2011","journal-title":"J Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103627","article-title":"The TIGIT\/CD226 axis regulates human T cell function","volume":"188","author":"Lozano","year":"2012","journal-title":"J Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903474106","article-title":"The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity","volume":"106","author":"Stanietsky","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201243072","article-title":"Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR","volume":"43","author":"Stanietsky","year":"2013","journal-title":"Eur J Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.673061","article-title":"Loss of CD96 expression as a marker of HIV-specific CD8(+) T-cell differentiation and dysfunction","volume":"12","author":"Bunet","year":"2021","journal-title":"Front Immunol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1002\/eji.201948405","article-title":"CD96 functions as a co-stimulatory receptor to enhance CD8(+) T cell activation and effector responses","volume":"50","author":"Chiang","year":"2020","journal-title":"Eur J Immunol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01177-06","article-title":"PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion","volume":"80","author":"Urbani","year":"2006","journal-title":"J Virol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.6.3637","article-title":"Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences","volume":"180","author":"Golden-Mason","year":"2008","journal-title":"J Immunol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911623","article-title":"Alterations in hepatocellular carcinoma-specific immune responses following hepatitis C virus elimination by direct-acting antivirals","volume":"23","author":"Li","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aba7918","article-title":"TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells","volume":"5","author":"Sekine","year":"2020","journal-title":"Sci Immunol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15050","article-title":"TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation","volume":"8","author":"Wieland","year":"2017","journal-title":"Nat Commun"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018016279","article-title":"TCF1 expression marks self-renewing human CD8(+) T cells","volume":"2","author":"Kratchmarov","year":"2018","journal-title":"Blood Adv"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00563-6","article-title":"TCF1 in T cell immunity: a broadened frontier","volume":"22","author":"Zhao","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.210.supp.239.17","article-title":"TCR signaling dynamically regulates TCF1 expression and effector differentiation","volume":"210","author":"Favret","year":"2023","journal-title":"J Immunol"},{"key":"B89","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.12.034","article-title":"Defining T cell states associated with response to checkpoint immunotherapy in melanoma","volume":"175","author":"Sade-Feldman","year":"2018","journal-title":"Cell"},{"key":"B90","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.immuni.2017.11.021","article-title":"Transcription factor IRF4 promotes CD8(+) T cell exhaustion and limits the development of memory-like T cells during chronic infection","volume":"47","author":"Man","year":"2017","journal-title":"Immunity"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201344279","article-title":"IRF4 at the crossroads of effector T-cell fate decision","volume":"44","author":"Huber","year":"2014","journal-title":"Eur J Immunol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200317","article-title":"Cutting edge: promoting T cell factor 1(+) T cell self-renewal to improve programmed cell death protein 1 blockade","volume":"209","author":"Wang","year":"2022","journal-title":"J Immunol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","article-title":"Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy","volume":"50","author":"Siddiqui","year":"2019","journal-title":"Immunity"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00817-w","article-title":"Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection","volume":"22","author":"Hensel","year":"2021","journal-title":"Nat Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.am2023-896","article-title":"Abstract 896: Investigating tissue-resident memory T cell differentiation of CAR T cells reveals an unexpected role for CD69","volume":"83","author":"Cheng","year":"2023","journal-title":"Cancer Res"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.3155546","article-title":"Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites","volume":"20","author":"Kumar","year":"2017","journal-title":"Cell Rep"},{"key":"B97","doi-asserted-by":"publisher","first-page":"6172","DOI":"10.1038\/s41598-017-06352-3","article-title":"Human intrahepatic CD69\u2009+\u2009CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity","volume":"7","author":"Stelma","year":"2017","journal-title":"Sci Rep"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900052","article-title":"The functional requirement for CD69 in establishment of resident memory CD8(+) T cells varies with tissue location","volume":"203","author":"Walsh","year":"2019","journal-title":"J Immunol"},{"key":"B99","first-page":"1","article-title":"PD-1\/PD-L1 checkpoint in lymphoprolipherative Malignancies: focus on critical points for tissue assessment","volume":"2","author":"Bianchi","year":"2017","journal-title":"ARC Journals"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.20900\/immunometab20220007","article-title":"Effects of PD-1 signaling on immunometabolic reprogramming","volume":"4","author":"Boussiotis","year":"2022","journal-title":"Immunometabolism"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1571892","article-title":"PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations","volume":"15","author":"Jiang","year":"2019","journal-title":"Hum Vaccin Immunother"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1163633","article-title":"The role of PD-1 signaling in health and immune-related diseases","volume":"14","author":"Chen","year":"2023","journal-title":"Front Immunol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1126\/science.291.5502.319","article-title":"Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice","volume":"291","author":"Nishimura","year":"2001","journal-title":"Science"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/s1471-4906(01)01888-9","article-title":"PD-1: an inhibitory immunoreceptor involved in peripheral tolerance","volume":"22","author":"Nishimura","year":"2001","journal-title":"Trends Immunol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.02.033","article-title":"Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization","volume":"134","author":"Nakamoto","year":"2008","journal-title":"Gastroenterology"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.141","article-title":"Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells","volume":"20","author":"Liu","year":"2013","journal-title":"Cell Death Differ"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2011.01.005","article-title":"The signaling tool box for tyrosine-based costimulation of lymphocytes","volume":"23","author":"Engels","year":"2011","journal-title":"Curr Opin Immunol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01072","article-title":"Coming of age: CD96 emerges as modulator of immune responses","volume":"9","author":"Georgiev","year":"2018","journal-title":"Front Immunol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1708329115","article-title":"CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells","volume":"115","author":"Stanko","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B110","unstructured":"A Study Investigating AGEN1777 in Participants With Advanced Solid Tumors ClinicalTrials.gov 2021 [updated 2024\u201308\u201320; cited 2025 13th June\n          \n          \n          \n          2021"},{"key":"B111","unstructured":"Study of the Safety and Effectiveness of GSK6097608 in Participants With Advanced Solid Tumors ClinicalTrials.gov2020 [updated 2025\u201303\u201314; cited 2025 13th June\n          \n          \n          \n          2020"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.76.12.6104-6113.2002","article-title":"Comprehensive analysis of CD8(+)-T-cell responses against hepatitis C virus reveals multiple unpredicted specificities","volume":"76","author":"Lauer","year":"2002","journal-title":"J Virol"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.832206","article-title":"CD8(+) T-cell exhaustion phenotype in chronic hepatitis C virus infection is associated with epitope sequence variation","volume":"13","author":"Osuch","year":"2022","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1883007\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:33:40Z","timestamp":1783920820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1883007\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":113,"alternative-id":["10.3389\/fimmu.2026.1883007"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1883007","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]},"article-number":"1883007"}}