{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:17:28Z","timestamp":1793643448925,"version":"4.5.1"},"reference-count":67,"publisher":"Rockefeller University Press","issue":"10","license":[{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P51 OD011132"],"award-info":[{"award-number":["P51 OD011132"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI030048"],"award-info":[{"award-number":["R01AI030048"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10 OD026799"],"award-info":[{"award-number":["S10 OD026799"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,3]]},"abstract":"<jats:p>Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-\u03b2 in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-\u03b2 signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-\u03b2 regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-\u03b2 also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-\u03b2 signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.<\/jats:p>","DOI":"10.1084\/jem.20211574","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T13:50:55Z","timestamp":1660830655000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":91,"title":["TGF-\u03b2 regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9714-8957","authenticated-orcid":true,"given":"Yinghong","family":"Hu","sequence":"first","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2513-1213","authenticated-orcid":true,"given":"William H.","family":"Hudson","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7624-5598","authenticated-orcid":true,"given":"Haydn T.","family":"Kissick","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 1"},{"name":"Winship Cancer Institute of Emory University, Atlanta, GA 2"},{"name":"Department of Urology, Emory University School of Medicine, Atlanta, GA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7441-9232","authenticated-orcid":true,"given":"Christopher B.","family":"Medina","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8182-8982","authenticated-orcid":true,"given":"Antonio P.","family":"Baptista","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium 4"},{"name":"Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium 5"},{"name":"Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5770-5085","authenticated-orcid":true,"given":"Chaoyu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8828-011X","authenticated-orcid":true,"given":"Wei","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 6"},{"name":"Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1495-9143","authenticated-orcid":true,"given":"Ronald N.","family":"Germain","sequence":"additional","affiliation":[{"name":"Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-908X","authenticated-orcid":true,"given":"Shannon J.","family":"Turley","sequence":"additional","affiliation":[{"name":"Genentech Inc., South San Francisco, CA 9"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-210X","authenticated-orcid":true,"given":"Nu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-2621","authenticated-orcid":true,"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"2025042817201374000_bib1","doi-asserted-by":"publisher","first-page":"265","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":"2025042817201374000_bib2","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"2025042817201374000_bib3","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1016\/j.immuni.2019.03.024","article-title":"Transforming growth factor-\u03b2 signaling in immunity and cancer","volume":"50","author":"Batlle","year":"2019","journal-title":"Immunity"},{"key":"2025042817201374000_bib4","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1089\/vim.2011.0079","article-title":"TGF-\u03b2 blockade does not improve control of an established persistent viral infection","volume":"25","author":"Boettler","year":"2012","journal-title":"Viral Immunol."},{"key":"2025042817201374000_bib5","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/s41586-018-0282-0","article-title":"The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells","volume":"559","author":"Borges da Silva","year":"2018","journal-title":"Nature"},{"key":"2025042817201374000_bib6","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti\u2013PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"2025042817201374000_bib7","doi-asserted-by":"publisher","first-page":"2520","DOI":"10.1084\/jem.20180684","article-title":"High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors","volume":"215","author":"Brummelman","year":"2018","journal-title":"J. Exp. Med."},{"key":"2025042817201374000_bib8","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/nature04882","article-title":"Kruppel-like factor 2 regulates thymocyte and T-cell migration","volume":"442","author":"Carlson","year":"2006","journal-title":"Nature"},{"key":"2025042817201374000_bib9","doi-asserted-by":"publisher","first-page":"18778","DOI":"10.1073\/pnas.1018994108","article-title":"CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2","volume":"108","author":"Chen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025042817201374000_bib10","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1002\/eji.200737157","article-title":"Opposing regulation of T cell function by Egr-1\/NAB2 and Egr-2\/Egr-3","volume":"38","author":"Collins","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2025042817201374000_bib11","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41590-019-0577-9","article-title":"The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity","volume":"21","author":"Dan","year":"2020","journal-title":"Nat. Immunol."},{"key":"2025042817201374000_bib12","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature05115","article-title":"PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"2025042817201374000_bib13","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1186\/s12859-016-1176-5","article-title":"FastProject: A tool for low-dimensional analysis of single-cell RNA-seq data","volume":"17","author":"DeTomaso","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"2025042817201374000_bib14","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/mi.2013.119","article-title":"Soluble CD83 ameliorates experimental colitis in mice","volume":"7","author":"Eckhardt","year":"2014","journal-title":"Mucosal Immunol."},{"key":"2025042817201374000_bib15","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1016\/j.immuni.2021.06.007","article-title":"Transforming growth factor-\u03b2-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection","volume":"54","author":"Gabriel","year":"2021","journal-title":"Immunity"},{"key":"2025042817201374000_bib16","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1038\/s41590-020-0791-5","article-title":"Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans","volume":"21","author":"Galletti","year":"2020","journal-title":"Nat. Immunol."},{"key":"2025042817201374000_bib17","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1084\/jem.187.9.1383","article-title":"Induction and exhaustion of lymphocytic choriomeningitis virus\u2013specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I\u2013peptide complexes","volume":"187","author":"Gallimore","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025042817201374000_bib18","doi-asserted-by":"publisher","first-page":"7060","DOI":"10.1128\/JVI.00164-12","article-title":"Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection","volume":"86","author":"Garidou","year":"2012","journal-title":"J. Virol."},{"key":"2025042817201374000_bib19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40425-018-0316-z","article-title":"Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations","volume":"6","author":"Gong","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"2025042817201374000_bib20","doi-asserted-by":"publisher","DOI":"10.5402\/2012\/682168","article-title":"CD200:CD200R-Mediated regulation of immunity","volume":"2012","author":"Gorczynski","year":"2012","journal-title":"ISRN Immunol."},{"key":"2025042817201374000_bib21","doi-asserted-by":"publisher","first-page":"301","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":"2025042817201374000_bib22","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/nature19317","article-title":"Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection","volume":"537","author":"He","year":"2016","journal-title":"Nature"},{"key":"2025042817201374000_bib23","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.4049\/jimmunol.1600802","article-title":"Soluble CD83 inhibits T cell activation by binding to the TLR4\/MD-2 complex on CD14(+) monocytes","volume":"198","author":"Horvatinovich","year":"2017","journal-title":"J. Immunol."},{"key":"2025042817201374000_bib24","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.immuni.2019.11.002","article-title":"Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection","volume":"51","author":"Hudson","year":"2019","journal-title":"Immunity"},{"key":"2025042817201374000_bib25","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","article-title":"Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy","volume":"537","author":"Im","year":"2016","journal-title":"Nature"},{"key":"2025042817201374000_bib26","doi-asserted-by":"publisher","first-page":"4292","DOI":"10.1073\/pnas.1917298117","article-title":"PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection","volume":"117","author":"Im","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025042817201374000_bib27","doi-asserted-by":"publisher","first-page":"14113","DOI":"10.1073\/pnas.1903520116","article-title":"Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade","volume":"116","author":"Jadhav","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025042817201374000_bib28","doi-asserted-by":"publisher","first-page":"2469","DOI":"10.1084\/jem.20090525","article-title":"T-bet\u2013dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow","volume":"206","author":"Jenne","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025042817201374000_bib29","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.immuni.2007.07.010","article-title":"Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor","volume":"27","author":"Joshi","year":"2007","journal-title":"Immunity"},{"key":"2025042817201374000_bib30","doi-asserted-by":"publisher","first-page":"211","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":"2025042817201374000_bib31","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1172\/JCI87041","article-title":"TGF-\u03b2 receptor maintains CD4 T helper cell identity during chronic viral infections","volume":"126","author":"Lewis","year":"2016","journal-title":"J. Clin. Invest."},{"key":"2025042817201374000_bib32","doi-asserted-by":"publisher","first-page":"385","DOI":"10.7497\/j.issn.2095-3941.2015.0015","article-title":"Mechanistic basis and clinical relevance of the role of transforming growth factor-\u03b2 in cancer","volume":"12","author":"Lin","year":"2015","journal-title":"Cancer Biol. Med."},{"key":"2025042817201374000_bib33","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1038\/s41590-020-0733-2","article-title":"Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Immunol."},{"key":"2025042817201374000_bib34","doi-asserted-by":"publisher","first-page":"11013","DOI":"10.1073\/pnas.1510119112","article-title":"Transforming growth factor-\u03b2 signaling is constantly shaping memory T-cell population","volume":"112","author":"Ma","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025042817201374000_bib67","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211538","article-title":"TGF-\u03b2 promotes stem-like T cells via enforcing their lymphoid tissue retention","volume":"219","author":"Ma","year":"2022","journal-title":"J. Exp. Med"},{"key":"2025042817201374000_bib35","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"2025042817201374000_bib36","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.immuni.2015.01.006","article-title":"The transcription factor NFAT promotes exhaustion of activated CD8\u207a T cells","volume":"42","author":"Martinez","year":"2015","journal-title":"Immunity"},{"key":"2025042817201374000_bib37","doi-asserted-by":"publisher","first-page":"8056","DOI":"10.1128\/JVI.68.12.8056-8063.1994","article-title":"CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection","volume":"68","author":"Matloubian","year":"1994","journal-title":"J. Virol."},{"key":"2025042817201374000_bib38","doi-asserted-by":"publisher","first-page":"457","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":"2025042817201374000_bib39","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/nature24993","article-title":"Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours","volume":"552","author":"Milner","year":"2017","journal-title":"Nature"},{"key":"2025042817201374000_bib40","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41591-022-01726-1","article-title":"PSMA-Targeting TGF\u03b2-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase 1 trial","volume":"28","author":"Narayan","year":"2022","journal-title":"Nat. Med."},{"key":"2025042817201374000_bib41","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/346629a0","article-title":"Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo","volume":"346","author":"Pircher","year":"1990","journal-title":"Nature"},{"key":"2025042817201374000_bib42","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.cell.2012.02.042","article-title":"The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor","volume":"149","author":"Powell","year":"2012","journal-title":"Cell"},{"key":"2025042817201374000_bib43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2249.2012.04623.x","article-title":"CD73 and adenosine generation in the creation of regulatory microenvironments","volume":"171","author":"Regateiro","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"2025042817201374000_bib44","doi-asserted-by":"publisher","first-page":"a022236","DOI":"10.1101\/cshperspect.a022236","article-title":"Regulation of the immune response by TGF-\u03b2: From conception to autoimmunity and infection","volume":"9","author":"Sanjabi","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2025042817201374000_bib45","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.immuni.2014.12.007","article-title":"Tissue-resident memory T cells","volume":"41","author":"Schenkel","year":"2014","journal-title":"Immunity"},{"key":"2025042817201374000_bib46","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","article-title":"TOX is a critical regulator of tumour-specific T cell differentiation","volume":"571","author":"Scott","year":"2019","journal-title":"Nature"},{"key":"2025042817201374000_bib47","doi-asserted-by":"publisher","first-page":"12410","DOI":"10.1073\/pnas.1905675116","article-title":"TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion","volume":"116","author":"Seo","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025042817201374000_bib48","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/s0092-8674(03)00432-x","article-title":"Mechanisms of TGF-\u03b2 signaling from cell membrane to the nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"2025042817201374000_bib49","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1038\/ni.2745","article-title":"Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells","volume":"14","author":"Skon","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025042817201374000_bib50","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.immuni.2018.08.002","article-title":"CD8+ T cell priming in established chronic viral infection preferentially directs differentiation of memory-like cells for sustained immunity","volume":"49","author":"Snell","year":"2018","journal-title":"Immunity"},{"key":"2025042817201374000_bib51","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1038\/nature25492","article-title":"TGF\u03b2 drives immune evasion in genetically reconstituted colon cancer metastasis","volume":"554","author":"Tauriello","year":"2018","journal-title":"Nature"},{"key":"2025042817201374000_bib52","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.immuni.2009.06.015","article-title":"Cell-intrinsic transforming growth factor-\u03b2 signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo","volume":"31","author":"Tinoco","year":"2009","journal-title":"Immunity"},{"key":"2025042817201374000_bib53","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti\u2013PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"2025042817201374000_bib54","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.immuni.2018.03.025","article-title":"T cell receptor-regulated TGF-\u03b2 type I receptor expression determines T cell quiescence and activation","volume":"48","author":"Tu","year":"2018","journal-title":"Immunity"},{"key":"2025042817201374000_bib55","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","article-title":"T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections","volume":"45","author":"Utzschneider","year":"2016","journal-title":"Immunity"},{"key":"2025042817201374000_bib56","doi-asserted-by":"publisher","first-page":"3454","DOI":"10.1016\/j.celrep.2018.03.020","article-title":"Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1","volume":"22","author":"Utzschneider","year":"2018","journal-title":"Cell Rep."},{"key":"2025042817201374000_bib57","doi-asserted-by":"publisher","first-page":"738","DOI":"10.3390\/cancers12030738","article-title":"Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence","volume":"12","author":"Vaddepally","year":"2020","journal-title":"Cancers"},{"key":"2025042817201374000_bib58","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1038\/s41467-021-23044-9","article-title":"Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance","volume":"12","author":"Wagle","year":"2021","journal-title":"Nat. Commun."},{"key":"2025042817201374000_bib59","doi-asserted-by":"publisher","first-page":"4911","DOI":"10.1128\/jvi.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J. Virol."},{"key":"2025042817201374000_bib60","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular signature of CD8+ T cell exhaustion during chronic viral infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"2025042817201374000_bib61","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1084\/jem.20160485","article-title":"The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment","volume":"214","author":"Williams","year":"2017","journal-title":"J. Exp. Med."},{"key":"2025042817201374000_bib62","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aai8593","article-title":"The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness","volume":"1","author":"Wu","year":"2016","journal-title":"Sci. Immunol."},{"key":"2025042817201374000_bib63","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025042817201374000_bib64","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.immuni.2019.10.009","article-title":"CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer","volume":"51","author":"Zander","year":"2019","journal-title":"Immunity"},{"key":"2025042817201374000_bib65","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/ni.2319","article-title":"TGF-\u03b2 signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation","volume":"13","author":"Zhang","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025042817201374000_bib66","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.immuni.2013.08.019","article-title":"Transforming growth factor-\u03b2 signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention","volume":"39","author":"Zhang","year":"2013","journal-title":"Immunity"}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20211574\/1441919\/jem_20211574.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20211574\/1441919\/jem_20211574.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T21:20:19Z","timestamp":1745875219000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/219\/10\/e20211574\/213409\/TGF-regulates-the-stem-like-state-of-PD-1-TCF-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,18]]},"references-count":67,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,10,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20211574","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,18]]},"article-number":"e20211574"}}