{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:36:17Z","timestamp":1791304577800,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.pbio.3002943","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000}}],"reference-count":146,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA243004"],"award-info":[{"award-number":["U01CA243004"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA243004"],"award-info":[{"award-number":["U01CA243004"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI151051"],"award-info":[{"award-number":["R01 AI151051"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production\/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002943","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T13:42:12Z","timestamp":1734442932000},"page":"e3002943","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7244-1337","authenticated-orcid":true,"given":"Matthew L.","family":"Lawton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M.","family":"Inge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin C.","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika L.","family":"Smith-Mahoney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante","family":"Bolzan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"McConney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Porter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrod","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Youssef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashasvi","family":"Tharani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xaralabos","family":"Varelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald V.","family":"Denis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson W.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dzmitry","family":"Padhorny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dima","family":"Kozakov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Siggers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wuchty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Snyder-Cappione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8995-246X","authenticated-orcid":true,"given":"Andrew","family":"Emili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"key":"pbio.3002943.ref001","doi-asserted-by":"crossref","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":"A Gallimore","year":"1998","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref002","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/362758a0","article-title":"Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells","volume":"362","author":"D Moskophidis","year":"1993","journal-title":"Nature"},{"key":"pbio.3002943.ref003","doi-asserted-by":"crossref","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":"AJ Zajac","year":"1998","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref004","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"DL Barber","year":"2006","journal-title":"Nature"},{"key":"pbio.3002943.ref005","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ni.1679","article-title":"Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection","volume":"10","author":"SD Blackburn","year":"2009","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref006","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1084\/jem.20081398","article-title":"Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection","volume":"205","author":"RB Jones","year":"2008","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref007","doi-asserted-by":"crossref","first-page":"e1005349","DOI":"10.1371\/journal.ppat.1005349","article-title":"TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.","volume":"12","author":"GM Chew","year":"2016","journal-title":"PLoS Pathog."},{"key":"pbio.3002943.ref008","doi-asserted-by":"crossref","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":"LM McLane","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"pbio.3002943.ref009","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining \u2018T cell exhaustion","volume":"19","author":"CU Blank","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"pbio.3002943.ref010","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"EJ Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"pbio.3002943.ref011","doi-asserted-by":"crossref","first-page":"e30938","DOI":"10.7554\/eLife.30938","article-title":"Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function","volume":"7","author":"M Bettonville","year":"2018","journal-title":"Elife"},{"key":"pbio.3002943.ref012","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s42255-020-00280-9","article-title":"Metabolic and epigenetic regulation of T-cell exhaustion.","volume":"2","author":"F Franco","year":"2020","journal-title":"Nat Metab."},{"key":"pbio.3002943.ref013","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.jaci.2018.02.042","article-title":"Immune checkpoint blockade therapy","volume":"142","author":"T Wieder","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"pbio.3002943.ref014","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.intimp.2018.06.001","article-title":"Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors","volume":"62","author":"KM Hargadon","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"pbio.3002943.ref015","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"SC Wei","year":"2018","journal-title":"Cancer Discov"},{"key":"pbio.3002943.ref016","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1056\/NEJMoa2024850","article-title":"Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma","volume":"384","author":"NC Munshi","year":"2021","journal-title":"N Engl J Med"},{"key":"pbio.3002943.ref017","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0140-6736(20)31366-0","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.","volume":"396","author":"JS Abramson","year":"2020","journal-title":"Lancet"},{"key":"pbio.3002943.ref018","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b\/2 open-label study.","volume":"398","author":"JG Berdeja","year":"2021","journal-title":"Lancet"},{"key":"pbio.3002943.ref019","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41408-021-00459-7","article-title":"CAR-T cell therapy: current limitations and potential strategies","volume":"11","author":"RC Sterner","year":"2021","journal-title":"Blood Cancer J"},{"key":"pbio.3002943.ref020","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2174\/1389201019666180418095526","article-title":"CAR T-cell Therapy: A New Era in Cancer Immunotherapy.","volume":"19","author":"AN Miliotou","year":"2018","journal-title":"Curr Pharm Biotechnol"},{"key":"pbio.3002943.ref021","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00428-018-2484-0","article-title":"Adoptive cellular therapies: the current landscape.","volume":"474","author":"MW Rohaan","year":"2019","journal-title":"Haanen JBAG.Virchows Arch."},{"key":"pbio.3002943.ref022","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/s40425-019-0805-8","article-title":"Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors","volume":"7","author":"S Das","year":"2019","journal-title":"J Immunother Cancer"},{"key":"pbio.3002943.ref023","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"O Khan","year":"2019","journal-title":"Nature"},{"key":"pbio.3002943.ref024","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/s12276-021-00568-0","article-title":"Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion","volume":"53","author":"W Seo","year":"2021","journal-title":"Exp Mol Med"},{"key":"pbio.3002943.ref025","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abe3348","article-title":"Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer","volume":"7","author":"A Cachot","year":"2021","journal-title":"Sci Adv"},{"key":"pbio.3002943.ref026","doi-asserted-by":"crossref","first-page":"e925135","DOI":"10.1155\/2012\/925135","article-title":"CD4+T Cells: Differentiation and Functions","volume":"2012","author":"RV Luckheeram","year":"2012","journal-title":"Clin Dev Immunol"},{"key":"pbio.3002943.ref027","doi-asserted-by":"crossref","first-page":"5742","DOI":"10.1158\/1078-0432.CCR-21-0206","article-title":"CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer","volume":"27","author":"AM Miggelbrink","year":"2021","journal-title":"Clin Cancer Res"},{"key":"pbio.3002943.ref028","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.20091918","article-title":"Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts","volume":"207","author":"SA Quezada","year":"2010","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref029","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1084\/jem.20150519","article-title":"CRTAM determines the CD4+ cytotoxic T lymphocyte lineage","volume":"213","author":"A Takeuchi","year":"2015","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref030","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41417-020-0183-x","article-title":"Revisiting the role of CD4+ T cells in cancer immunotherapy\u2014new insights into old paradigms","volume":"28","author":"RE Tay","year":"2021","journal-title":"Cancer Gene Ther"},{"key":"pbio.3002943.ref031","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1084\/jem.20091921","article-title":"Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma","volume":"207","author":"Y Xie","year":"2010","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref032","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1172\/JCI67428","article-title":"CD4+ follicular helper T cell infiltration predicts breast cancer survival","volume":"123","author":"C Gu-Trantien","year":"2013","journal-title":"J Clin Invest"},{"key":"pbio.3002943.ref033","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1182\/blood-2006-10-051318","article-title":"CD4 cells can be more efficient at tumor rejection than CD8 cells","volume":"109","author":"A Perez-Diez","year":"2007","journal-title":"Blood"},{"key":"pbio.3002943.ref034","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1182\/bloodadvances.2019000600","article-title":"T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma","volume":"3","author":"AL Garfall","year":"2019","journal-title":"Blood Adv"},{"key":"pbio.3002943.ref035","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.humpath.2017.09.012","article-title":"The CD4\/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer","volume":"69","author":"K Wang","year":"2017","journal-title":"Hum Pathol"},{"key":"pbio.3002943.ref036","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.gpb.2019.03.002","article-title":"Single-cell Analysis of CAR-T Cell Activation Reveals A Mixed TH1\/TH2 Response Independent of Differentiation.","volume":"17","author":"I Xhangolli","year":"2019","journal-title":"Genom Proteom Bioinform"},{"key":"pbio.3002943.ref037","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature22991","article-title":"An immunogenic personal neoantigen vaccine for patients with melanoma","volume":"547","author":"PA Ott","year":"2017","journal-title":"Nature"},{"key":"pbio.3002943.ref038","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature23003","article-title":"Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer","volume":"547","author":"U Sahin","year":"2017","journal-title":"Nature"},{"key":"pbio.3002943.ref039","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/imm.12109","article-title":"CD4+ T-cell inhibitory ligands: a tool for characterizing dysfunctional CD4+ T cells during chronic infection","volume":"140","author":"C Dow","year":"2013","journal-title":"Immunology"},{"key":"pbio.3002943.ref040","doi-asserted-by":"crossref","first-page":"21182","DOI":"10.1073\/pnas.1118450109","article-title":"Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection","volume":"108","author":"RD Aubert","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pbio.3002943.ref041","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.immuni.2014.01.005","article-title":"Molecular and Transcriptional Basis of CD4+ T Cell Dysfunction during Chronic Infection","volume":"40","author":"A Crawford","year":"2014","journal-title":"Immunity"},{"key":"pbio.3002943.ref042","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1007\/s10495-014-1084-y","article-title":"Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes","volume":"20","author":"M Barathan","year":"2015","journal-title":"Apoptosis"},{"key":"pbio.3002943.ref043","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.4049\/jimmunol.1101165","article-title":"Functional Exhaustion of CD4+ T Lymphocytes during Primary Cytomegalovirus Infection","volume":"189","author":"P Antoine","year":"2012","journal-title":"J Immunol"},{"key":"pbio.3002943.ref044","doi-asserted-by":"crossref","first-page":"10661","DOI":"10.1128\/JVI.00056-12","article-title":"HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term","volume":"86","author":"B Vingert","year":"2012","journal-title":"J Virol"},{"key":"pbio.3002943.ref045","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/ni1515","article-title":"Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction","volume":"8","author":"DE Kaufmann","year":"2007","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref046","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/1743-422X-8-113","article-title":"Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection","volume":"8","author":"W Wu","year":"2011","journal-title":"Virol J"},{"key":"pbio.3002943.ref047","first-page":"e47648","article-title":"Upregulation of the Tim-3\/Galectin-9","volume":"7","author":"G Nebbia","year":"2012","journal-title":"Pathway of T Cell Exhaustion in Chronic Hepatitis B Virus Infection. PLoS ONE"},{"key":"pbio.3002943.ref048","doi-asserted-by":"crossref","first-page":"10514","DOI":"10.1128\/JVI.79.16.10514-10527.2005","article-title":"Intrinsic Functional Dysregulation of CD4 T Cells Occurs Rapidly following Persistent Viral Infection","volume":"79","author":"DG Brooks","year":"2005","journal-title":"J Virol"},{"key":"pbio.3002943.ref049","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1084\/jem.20121416","article-title":"PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis","volume":"210","author":"BH Zinselmeyer","year":"2013","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref050","doi-asserted-by":"crossref","first-page":"e0123332","DOI":"10.1371\/journal.pone.0123332","article-title":"An Exhaustion-Like Phenotype Constrains the Activity of CD4+ T Cells Specific for a Self and Melanoma Antigen.","volume":"10","author":"MP Rausch","year":"2015","journal-title":"PLoS ONE."},{"key":"pbio.3002943.ref051","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12879-019-3743-7","article-title":"Immune signatures for HIV-1 and HIV-2 induced CD4+T cell dysregulation in an Indian cohort","volume":"19","author":"S Salwe","year":"2019","journal-title":"BMC Infect Dis"},{"key":"pbio.3002943.ref052","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1468-1293.2005.00307.x","article-title":"Dysregulation of CD28 and CTLA-4 expression by CD4 T cells from previously immunodeficient HIV-infected patients with sustained virological responses to highly active antiretroviral therapy.","volume":"6","author":"S Stone","year":"2005","journal-title":"HIV Med."},{"key":"pbio.3002943.ref053","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/s41590-019-0312-6","article-title":"Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade","volume":"20","author":"BC Miller","year":"2019","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref054","first-page":"4234","article-title":"CD4+ T cell exhaustion leads to adoptive transfer therapy failure which can be prevented by immune checkpoint blockade","volume":"10","author":"J Fu","year":"2020","journal-title":"Am J Cancer Res"},{"key":"pbio.3002943.ref055","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/978-1-0716-0171-6_6","volume-title":"Immuno-Oncology: Cellular and Translational Approaches","author":"LS Dunsford","year":"2020"},{"key":"pbio.3002943.ref056","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.isci.2018.03.009","article-title":"YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted Chronically Stimulated Human T Cells.","volume":"2","author":"MY Balkhi","year":"2018","journal-title":"iScience."},{"key":"pbio.3002943.ref057","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/1878-0261.13103","article-title":"PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.","volume":"16","author":"L Simula","year":"2022","journal-title":"Mol Oncol."},{"key":"pbio.3002943.ref058","doi-asserted-by":"crossref","first-page":"e1008555","DOI":"10.1371\/journal.ppat.1008555","article-title":"Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation.","volume":"16","author":"M Zhao","year":"2020","journal-title":"PLoS Pathog."},{"key":"pbio.3002943.ref059","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1038\/s41556-022-00942-8","article-title":"Dapl1 controls NFATc2 activation to regulate CD8+ T cell exhaustion and responses in chronic infection and cancer","volume":"24","author":"L Zhu","year":"2022","journal-title":"Nat Cell Biol"},{"key":"pbio.3002943.ref060","doi-asserted-by":"crossref","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":"J-C Beltra","year":"2020","journal-title":"Immunity"},{"key":"pbio.3002943.ref061","doi-asserted-by":"crossref","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":"EJ Wherry","year":"2007","journal-title":"Immunity"},{"key":"pbio.3002943.ref062","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"EJ Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref063","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3390\/genes13040693","article-title":"G-Protein Subunit Gamma 4 as a Potential Biomarker for Predicting the Response of Chemotherapy and Immunotherapy in Bladder Cancer.","volume":"13","author":"L Duan","year":"2022","journal-title":"Genes (Basel)."},{"key":"pbio.3002943.ref064","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1084\/jem.20071944","article-title":"Development of all CD4 T lineages requires nuclear factor TOX","volume":"205","author":"P Aliahmad","year":"2008","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref065","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.4049\/jimmunol.1101474","article-title":"TOX Is Required for Development of the CD4 T Cell Lineage Gene Program","volume":"187","author":"P Aliahmad","year":"2011","journal-title":"J Immunol"},{"key":"pbio.3002943.ref066","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1172\/JCI90895","article-title":"Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification","volume":"127","author":"CE Widjaja","journal-title":"J Clin Invest"},{"key":"pbio.3002943.ref067","doi-asserted-by":"crossref","first-page":"5529","DOI":"10.1093\/nar\/gkf682","article-title":"Genome-wide analysis of mRNA decay in resting and activated primary human T lymphocytes","volume":"30","author":"A Raghavan","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref068","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/iub.356","article-title":"Emerging roles of prostanoids in T cell-mediated immunity","volume":"62","author":"D Sakata","year":"2010","journal-title":"IUBMB Life"},{"key":"pbio.3002943.ref069","doi-asserted-by":"crossref","first-page":"e3000072","DOI":"10.1371\/journal.pbio.3000072","article-title":"Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts","volume":"17","author":"K Schaeuble","year":"2019","journal-title":"PLoS Biol"},{"key":"pbio.3002943.ref070","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/s41590-020-0725-2","article-title":"Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen","volume":"21","author":"SA Vardhana","year":"2020","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref071","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.278.5343.1638","article-title":"Nuclear Accumulation of NFAT4 Opposed by the JNK Signal Transduction Pathway","volume":"278","author":"C-W Chow","year":"1997","journal-title":"Science"},{"key":"pbio.3002943.ref072","doi-asserted-by":"crossref","first-page":"27412","DOI":"10.1074\/jbc.273.42.27412","article-title":"AKAP79 Inhibits Calcineurin through a Site Distinct from the Immunophilin-binding Region *","volume":"273","author":"A Kashishian","year":"1998","journal-title":"J Biol Chem"},{"key":"pbio.3002943.ref073","doi-asserted-by":"crossref","first-page":"16816","DOI":"10.1016\/S0021-9258(18)41856-X","article-title":"Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins. Characterization of AKAP 79","volume":"267","author":"DW Carr","year":"1992","journal-title":"J Biol Chem"},{"key":"pbio.3002943.ref074","first-page":"4","article-title":"The Vitamin D Receptor and T Cell Function","author":"M Kongsbak","year":"2013","journal-title":"Front Immunol"},{"key":"pbio.3002943.ref075","doi-asserted-by":"crossref","first-page":"e003477","DOI":"10.1136\/jitc-2021-003477","article-title":"1\u03b1,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.","volume":"10","author":"P Li","year":"2022","journal-title":"J Immunother Cancer"},{"key":"pbio.3002943.ref076","doi-asserted-by":"crossref","first-page":"20191","DOI":"10.1038\/s41598-020-77093-z","article-title":"Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers.","volume":"10","author":"A Jain","year":"2020","journal-title":"Sci Rep."},{"key":"pbio.3002943.ref077","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00210-022-02210-w","article-title":"Vitamin D can reduce severity in COVID-19 through regulation of PD-L1","volume":"395","author":"H. Aygun","year":"2022","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"pbio.3002943.ref078","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41467-019-14137-7","article-title":"Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection.","volume":"11","author":"V Barili","year":"2020","journal-title":"Nat Commun."},{"key":"pbio.3002943.ref079","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/ni0405-368","article-title":"MAPK p38: alternative and nonstressful in T cells","volume":"6","author":"CE Rudd","year":"2005","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref080","doi-asserted-by":"crossref","first-page":"95103","DOI":"10.1172\/jci.insight.95103","article-title":"Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy","volume":"2","author":"CA Klebanoff","year":"2017","journal-title":"JCI Insight"},{"key":"pbio.3002943.ref081","first-page":"2379","article-title":"Akt inhibition at the initial stage of CAR-T preparation enhances the CAR-positive expression rate, memory phenotype and in vivo efficacy","volume":"9","author":"Q Zhang","year":"2019","journal-title":"Am J Cancer Res"},{"key":"pbio.3002943.ref082","doi-asserted-by":"crossref","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","article-title":"Cluster analysis and display of genome-wide expression patterns","volume":"95","author":"MB Eisen","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pbio.3002943.ref083","doi-asserted-by":"crossref","first-page":"W171","DOI":"10.1093\/nar\/gky458","article-title":"eXpression2Kinases (X2K) Web: linking expression signatures to upstream cell signaling networks.","volume":"46","author":"DJB Clarke","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref084","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.3389\/fimmu.2018.02809","article-title":"The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment.","volume":"9","author":"L Agresta","year":"2018","journal-title":"Front Immunol."},{"key":"pbio.3002943.ref085","article-title":"Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases.","volume":"12","author":"L Sun","year":"2021","journal-title":"Front Immunol."},{"key":"pbio.3002943.ref086","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01810","article-title":"Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses.","volume":"9","author":"AB Morris","year":"2018","journal-title":"Front Immunol."},{"key":"pbio.3002943.ref087","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1182\/blood-2012-09-457531","article-title":"T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production","volume":"121","author":"JC Riches","year":"2013","journal-title":"Blood"},{"key":"pbio.3002943.ref088","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4049\/jimmunol.2000300","article-title":"SLAMF7 Signaling Reprograms T Cells toward Exhaustion in the Tumor Microenvironment","volume":"206","author":"P O\u2019Connell","year":"2021","journal-title":"J Immunol"},{"key":"pbio.3002943.ref089","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/ni.2610","article-title":"T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10","volume":"14","author":"E Bandala-Sanchez","year":"2013","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref090","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jss.2014.09.035","article-title":"Siglec-10 is associated with survival and natural killer cell dysfunction in hepatocellular carcinoma","volume":"194","author":"P Zhang","year":"2015","journal-title":"J Surg Res"},{"key":"pbio.3002943.ref091","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.humimm.2020.01.009","article-title":"Siglec-10 expression is up-regulated in activated human CD4+ T cells","volume":"81","author":"E Bandala-Sanchez","year":"2020","journal-title":"Hum Immunol"},{"key":"pbio.3002943.ref092","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/eji.200839028","article-title":"B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction","volume":"39","author":"J Leitner","year":"2009","journal-title":"Eur J Immunol"},{"key":"pbio.3002943.ref093","article-title":"VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers.","volume":"4","author":"CG Kim","year":"2019","journal-title":"Sci Immunol."},{"key":"pbio.3002943.ref094","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.645242","article-title":"Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy.","volume":"12","author":"GO Rangel Rivera","year":"2021","journal-title":"Front Immunol"},{"key":"pbio.3002943.ref095","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nri.2016.80","article-title":"Regulatory circuits of T cell function in cancer","volume":"16","author":"DE Speiser","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"pbio.3002943.ref096","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.15252\/embj.201490786","article-title":"Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion","volume":"34","author":"M Giordano","year":"2015","journal-title":"EMBO J"},{"key":"pbio.3002943.ref097","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41586-018-0206-z","article-title":"Induction and transcriptional regulation of the co-inhibitory gene module in T cells","volume":"558","author":"N Chihara","year":"2018","journal-title":"Nature"},{"key":"pbio.3002943.ref098","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1084\/jem.20150194","article-title":"Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection","volume":"212","author":"KD Omilusik","year":"2015","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref099","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1084\/jem.20150186","article-title":"The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection","volume":"212","author":"CX Dominguez","year":"2015","journal-title":"J Exp Med"},{"key":"pbio.3002943.ref100","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.it.2019.03.001","article-title":"ZEBs: Novel Players in Immune Cell Development and Function","volume":"40","author":"CL Scott","year":"2019","journal-title":"Trends Immunol"},{"key":"pbio.3002943.ref101","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.immuni.2012.08.021","article-title":"Network Analysis Reveals Centrally Connected Genes and Pathways Involved in CD8+ T Cell Exhaustion versus Memory","volume":"37","author":"TA Doering","year":"2012","journal-title":"Immunity"},{"key":"pbio.3002943.ref102","first-page":"ec58","article-title":"Enhancing cytotoxic T cells by inhibiting GSK3.","volume":"9","author":"JF Foley","year":"2016","journal-title":"Sci Signal"},{"key":"pbio.3002943.ref103","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.immuni.2016.01.018","article-title":"Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8+ Cytolytic T Cell Responses","volume":"44","author":"A Taylor","year":"2016","journal-title":"Immunity"},{"key":"pbio.3002943.ref104","doi-asserted-by":"crossref","first-page":"3832","DOI":"10.1128\/MCB.00032-09","article-title":"RelB NF-\u03baB Represses Estrogen Receptor \u03b1 Expression via Induction of the Zinc Finger Protein Blimp1","volume":"29","author":"X Wang","year":"2009","journal-title":"Mol Cell Biol"},{"key":"pbio.3002943.ref105","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.741302","article-title":"Easy or Not\u2014The Advances of EZH2 in Regulating T Cell Development, Differentiation, and Activation in Antitumor Immunity.","volume":"12","author":"J Huang","year":"2021","journal-title":"Front Immunol."},{"key":"pbio.3002943.ref106","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.3390\/cancers13164148","article-title":"PD-L1 Overexpression, SWI\/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells.","volume":"13","author":"I Jancewicz","year":"2021","journal-title":"Cancers"},{"key":"pbio.3002943.ref107","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1172\/JCI99760","article-title":"Modulation of EZH2 expression in T cells improves efficacy of anti\u2013CTLA-4 therapy","volume":"128","author":"S Goswami","journal-title":"J Clin Invest"},{"key":"pbio.3002943.ref108","doi-asserted-by":"crossref","first-page":"100098","DOI":"10.1016\/j.xgen.2022.100098","article-title":"CASCADE: high-throughput characterization of regulatory complex binding altered by non-coding variants","volume":"2","author":"D Bray","year":"2022","journal-title":"Cell Genom"},{"key":"pbio.3002943.ref109","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nrneph.2015.115","article-title":"T-cell exhaustion limits immune reactivity and is associated with good prognosis in autoimmune disease.","volume":"11","author":"EF Carney","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"pbio.3002943.ref110","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/nature14468","article-title":"T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection","volume":"523","author":"EF McKinney","year":"2015","journal-title":"Nature"},{"key":"pbio.3002943.ref111","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.2217\/imt-2017-0134","article-title":"Modulation of antitumor immunity with histone deacetylase inhibitors","volume":"9","author":"TR McCaw","year":"2017","journal-title":"Immunotherapy"},{"key":"pbio.3002943.ref112","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1007\/s00262-019-02430-9","article-title":"Histone deacetylase inhibition promotes intratumoral CD8+ T cell responses, sensitizing murine breast tumors to anti-PD1","volume":"68","author":"TR McCaw","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"pbio.3002943.ref113","doi-asserted-by":"crossref","first-page":"165.23","DOI":"10.4049\/jimmunol.204.Supp.165.23","article-title":"Elucidating the Role of HDACs in T Cell Biology and Comparing Distinct HDAC Inhibitors in Augmenting Responses to Cancer Immunotherapy","volume":"204","author":"TA Triplett","year":"2020","journal-title":"J Immunol"},{"key":"pbio.3002943.ref114","doi-asserted-by":"crossref","first-page":"13500","DOI":"10.1093\/nar\/gku1228","article-title":"Prediction of DNA binding motifs from 3D models of transcription factors; identifying TLX3 regulated genes","volume":"42","author":"M Pujato","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref115","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.cell.2012.12.009","article-title":"DNA-binding specificities of human transcription factors","volume":"152","author":"A Jolma","year":"2013","journal-title":"Cell"},{"key":"pbio.3002943.ref116","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nature11245","article-title":"Architecture of the human regulatory network derived from ENCODE data","volume":"489","author":"MB Gerstein","year":"2012","journal-title":"Nature"},{"key":"pbio.3002943.ref117","doi-asserted-by":"crossref","first-page":"D195","DOI":"10.1093\/nar\/gks1089","article-title":"HOCOMOCO: a comprehensive collection of human transcription factor binding sites models","volume":"41","author":"IV Kulakovskiy","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref118","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41586-019-0979-8","article-title":"Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction","volume":"567","author":"X Liu","year":"2019","journal-title":"Nature"},{"key":"pbio.3002943.ref119","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"J Chen","year":"2019","journal-title":"Nature"},{"key":"pbio.3002943.ref120","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41586-018-0597-x","article-title":"IRE1\u03b1\u2013XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity","volume":"562","author":"M Song","year":"2018","journal-title":"Nature"},{"key":"pbio.3002943.ref121","doi-asserted-by":"crossref","first-page":"100189","DOI":"10.1016\/j.mcpro.2021.100189","article-title":"Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite\u2013Protein Physical Interaction Subnetworks Altered in Cancer","volume":"21","author":"BC Blum","year":"2022","journal-title":"Mol Cell Proteomics"},{"key":"pbio.3002943.ref122","doi-asserted-by":"crossref","first-page":"20181","DOI":"10.1074\/jbc.M802559200","article-title":"Selenoproteins Mediate T Cell Immunity through an Antioxidant Mechanism","volume":"283","author":"RK Shrimali","year":"2008","journal-title":"J Biol Chem"},{"key":"pbio.3002943.ref123","doi-asserted-by":"crossref","first-page":"a002428","DOI":"10.1101\/cshperspect.a002428","article-title":"Lipid Signaling in T-Cell Development and Function","volume":"2","author":"YH Huang","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"pbio.3002943.ref124","doi-asserted-by":"crossref","first-page":"8191","DOI":"10.4049\/jimmunol.179.12.8191","article-title":"Hyaluronan Synthesis Is Required for IL-2-Mediated T Cell Proliferation","volume":"179","author":"CL Mahaffey","year":"2007","journal-title":"J Immunol"},{"key":"pbio.3002943.ref125","doi-asserted-by":"crossref","first-page":"e1003123","DOI":"10.1371\/journal.pcbi.1003123","article-title":"Predicting Network Activity from High Throughput Metabolomics.","volume":"9","author":"S Li","year":"2013","journal-title":"PLoS Comput Biol."},{"issue":"07","key":"pbio.3002943.ref126","article-title":"Single Cell Portal: an interactive home for single-cell genomics data.","volume":"2023","author":"L Tarhan","year":"2023"},{"key":"pbio.3002943.ref127","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/s41588-021-00911-1","article-title":"A single-cell and spatially resolved atlas of human breast cancers","volume":"53","author":"SZ Wu","year":"2021","journal-title":"Nat Genet"},{"key":"pbio.3002943.ref128","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12918-015-0225-4","article-title":"A multi-omic analysis of human na\u00efve CD4+ T cells","volume":"9","author":"CJ Mitchell","year":"2015","journal-title":"BMC Syst Biol"},{"key":"pbio.3002943.ref129","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.tem.2016.01.001","article-title":"XBP1: A Pivotal Transcriptional Regulator of Glucose and Lipid Metabolism","volume":"27","author":"C Piperi","year":"2016","journal-title":"Trends Endocrinol Metab"},{"key":"pbio.3002943.ref130","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/s41591-018-0057-z","article-title":"A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade","volume":"24","author":"DS Thommen","year":"2018","journal-title":"Nat Med"},{"key":"pbio.3002943.ref131","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41590-020-00834-9","article-title":"Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion","volume":"22","author":"NE Scharping","year":"2021","journal-title":"Nat Immunol"},{"key":"pbio.3002943.ref132","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/iub.1084","article-title":"Selenium-containing amino acids as direct and indirect antioxidants","volume":"64","author":"AS Rahmanto","year":"2012","journal-title":"IUBMB Life"},{"key":"pbio.3002943.ref133","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations.","volume":"8","author":"JA Seidel","year":"2018","journal-title":"Front Oncol."},{"key":"pbio.3002943.ref134","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s13046-019-1259-z","article-title":"Combination of CTLA-4 and PD-1 blockers for treatment of cancer","volume":"38","author":"A. Rotte","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"pbio.3002943.ref135","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved Survival with Ipilimumab in Patients with Metastatic Melanoma","volume":"363","author":"FS Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"pbio.3002943.ref136","doi-asserted-by":"crossref","first-page":"508","DOI":"10.4161\/cib.3.6.13495","article-title":"Multifaceted regulation of T cells by CD44.","volume":"3","author":"BJ Baaten","year":"2010","journal-title":"Commun Integr Biol"},{"key":"pbio.3002943.ref137","article-title":"CD4 CTL, a Cytotoxic Subset of CD4+ T Cells","volume":"8","author":"A Takeuchi","year":"2017","journal-title":"Their Differentiation and Function. Front Immunol"},{"key":"pbio.3002943.ref138","doi-asserted-by":"crossref","first-page":"e1004879","DOI":"10.1371\/journal.pcbi.1004879","article-title":"Network-Based Interpretation of Diverse High-Throughput Datasets through the Omics Integrator Software Package","volume":"12","author":"N Tuncbag","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"pbio.3002943.ref139","first-page":"D498","article-title":"The reactome pathway knowledgebase","volume":"48","author":"B Jassal","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref140","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref141","first-page":"D504","article-title":"SIGNOR 2.0, the SIGnaling Network Open Resource 2.0: 2019 update","volume":"48","author":"L Licata","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref142","doi-asserted-by":"crossref","first-page":"741","DOI":"10.15252\/msb.20145141","article-title":"Intercellular network structure and regulatory motifs in the human hematopoietic system","volume":"10","author":"W Qiao","year":"2014","journal-title":"Mol Syst Biol"},{"key":"pbio.3002943.ref143","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1093\/nar\/gkz020","article-title":"NextPBM: a platform to study cell-specific transcription factor binding and cooperativity","volume":"47","author":"N Mohaghegh","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pbio.3002943.ref144","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-0716-1669-7_4","article-title":"High-Throughput Analysis of the Cell and DNA Site-Specific Binding of Native NF-\u03baB Dimers Using Nuclear Extract Protein-Binding Microarrays (NextPBMs).","volume":"2366","author":"H Hook","year":"2021","journal-title":"Methods Mol Biol"},{"key":"pbio.3002943.ref145","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nprot.2008.195","article-title":"Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors.","volume":"4","author":"MF Berger","year":"2009","journal-title":"Nat Protoc"},{"key":"pbio.3002943.ref146","doi-asserted-by":"crossref","first-page":"R24","DOI":"10.1186\/gb-2007-8-2-r24","article-title":"Quantifying similarity between motifs","volume":"8","author":"S Gupta","year":"2007","journal-title":"Genome Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3002943","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3002943","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T13:44:55Z","timestamp":1736171095000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3002943"}},"subtitle":[],"editor":[{"given":"Avinash","family":"Bhandoola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,17]]},"references-count":146,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3002943","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,17]]}}}