{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:32:40Z","timestamp":1791282760881,"version":"4.1.0"},"reference-count":48,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,5,9]]},"abstract":"<jats:p>CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.<\/jats:p>","DOI":"10.1084\/jem.20101773","type":"journal-article","created":{"date-parts":[[2011,5,2]],"date-time":"2011-05-02T23:06:17Z","timestamp":1304377577000},"page":"987-999","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":315,"title":["Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells"],"prefix":"10.1084","volume":"208","author":[{"given":"Laura M.","family":"Fahey","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Elsaesser","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris D.","family":"Fistonich","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorian B.","family":"McGavern","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics 1 and 2"},{"name":"UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2011,5,2]]},"reference":[{"key":"2023072600444986500_bib1","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":"2023072600444986500_bib2","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1128\/jvi.68.7.4700-4704.1994","article-title":"Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice","volume":"68","author":"Battegay","year":"1994","journal-title":"J. Virol."},{"key":"2023072600444986500_bib3","doi-asserted-by":"publisher","first-page":"e1000080","DOI":"10.1371\/journal.pbio.1000080","article-title":"Impaired antibody response causes persistence of prototypic T cell-contained virus","volume":"7","author":"Bergthaler","year":"2009","journal-title":"PLoS Biol."},{"key":"2023072600444986500_bib4","doi-asserted-by":"publisher","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":"Brooks","year":"2005","journal-title":"J. Virol."},{"key":"2023072600444986500_bib5","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1172\/JCI26856","article-title":"Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection","volume":"116","author":"Brooks","year":"2006","journal-title":"J. Clin. Invest."},{"key":"2023072600444986500_bib6","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1038\/nm1492","article-title":"Interleukin-10 determines viral clearance or persistence in vivo","volume":"12","author":"Brooks","year":"2006","journal-title":"Nat. Med."},{"key":"2023072600444986500_bib7","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1084\/jem.193.3.297","article-title":"Impairment of CD4+ T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants","volume":"193","author":"Ciurea","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2010.07.015","article-title":"Follicular Helper T Cell Differentiation Requires Continuous Antigen Presentation that Is Independent of Unique B Cell Signaling","volume":"33","author":"Deenick","year":"2010","journal-title":"Immunity."},{"key":"2023072600444986500_bib9","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1126\/science.1174182","article-title":"IL-21 is required to control chronic viral infection","volume":"324","author":"Elsaesser","year":"2009","journal-title":"Science."},{"key":"2023072600444986500_bib10","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/ni.1704","article-title":"The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding","volume":"10","author":"Fazilleau","year":"2009","journal-title":"Nat. Immunol."},{"key":"2023072600444986500_bib11","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/S0092-8674(00)81798-5","article-title":"A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen","volume":"87","author":"F\u00f6rster","year":"1996","journal-title":"Cell."},{"key":"2023072600444986500_bib12","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1126\/science.1172815","article-title":"IL-21R on T cells is critical for sustained functionality and control of chronic viral infection","volume":"324","author":"Fr\u00f6hlich","year":"2009","journal-title":"Science."},{"key":"2023072600444986500_bib13","doi-asserted-by":"crossref","first-page":"477","DOI":"10.4049\/jimmunol.170.1.477","article-title":"Ablation of CD8 and CD4 T cell responses by high viral loads","volume":"170","author":"Fuller","year":"2003","journal-title":"J. Immunol."},{"key":"2023072600444986500_bib14","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1084\/jem.187.10.1647","article-title":"Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides","volume":"187","author":"Gallimore","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib15","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.immuni.2005.01.005","article-title":"Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling","volume":"22","author":"Hahm","year":"2005","journal-title":"Immunity."},{"key":"2023072600444986500_bib16","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.4049\/jimmunol.179.8.5099","article-title":"Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation","volume":"179","author":"Haynes","year":"2007","journal-title":"J. Immunol."},{"key":"2023072600444986500_bib17","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.immuni.2009.12.004","article-title":"Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions","volume":"32","author":"Hegazy","year":"2010","journal-title":"Immunity."},{"key":"2023072600444986500_bib18","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1189\/jlb.0909639","article-title":"c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells","volume":"87","author":"Hiramatsu","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2023072600444986500_bib19","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/ni911","article-title":"Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections","volume":"4","author":"Hunziker","year":"2003","journal-title":"Nat. Immunol."},{"key":"2023072600444986500_bib20","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation","volume":"325","author":"Johnston","year":"2009","journal-title":"Science."},{"key":"2023072600444986500_bib21","doi-asserted-by":"crossref","first-page":"7109","DOI":"10.4049\/jimmunol.175.11.7109","article-title":"CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses","volume":"175","author":"Junt","year":"2005","journal-title":"J. Immunol."},{"key":"2023072600444986500_bib22","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/S0092-8674(02)01139-X","article-title":"Molecular and functional profiling of memory CD8 T cell differentiation","volume":"111","author":"Kaech","year":"2002","journal-title":"Cell."},{"key":"2023072600444986500_bib23","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1084\/jem.20090313","article-title":"IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells","volume":"206","author":"King","year":"2009","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib24","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1038\/ni1241","article-title":"T cells and viral persistence: lessons from diverse infections","volume":"6","author":"Klenerman","year":"2005","journal-title":"Nat. Immunol."},{"key":"2023072600444986500_bib25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s00281-009-0194-z","article-title":"Signals that influence T follicular helper cell differentiation and function","volume":"32","author":"Linterman","year":"2010","journal-title":"Semin. Immunopathol."},{"key":"2023072600444986500_bib26","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1084\/jem.20091738","article-title":"IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses","volume":"207","author":"Linterman","year":"2010","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib27","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/ni1227","article-title":"Initial T cell frequency dictates memory CD8+ T cell lineage commitment","volume":"6","author":"Marzo","year":"2005","journal-title":"Nat. Immunol."},{"key":"2023072600444986500_bib28","doi-asserted-by":"crossref","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":"2023072600444986500_bib29","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity."},{"key":"2023072600444986500_bib30","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science."},{"key":"2023072600444986500_bib31","doi-asserted-by":"publisher","first-page":"8252","DOI":"10.1073\/pnas.88.18.8252","article-title":"Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure","volume":"88","author":"Odermatt","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072600444986500_bib32","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1002\/(SICI)1521-4141(199801)28:01&lt;390::AID-IMMU390&gt;3.0.CO;2-O","article-title":"Virus-specific MHC-class II-restricted TCR-transgenic mice: effects on humoral and cellular immune responses after viral infection","volume":"28","author":"Oxenius","year":"1998","journal-title":"Eur. J. Immunol."},{"key":"2023072600444986500_bib33","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1126\/science.1077002","article-title":"A critical role for IL-21 in regulating immunoglobulin production","volume":"298","author":"Ozaki","year":"2002","journal-title":"Science."},{"key":"2023072600444986500_bib34","doi-asserted-by":"publisher","first-page":"797","DOI":"10.4049\/jimmunol.0901233","article-title":"Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells","volume":"183","author":"Pot","year":"2009","journal-title":"J. Immunol."},{"key":"2023072600444986500_bib35","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.mib.2004.06.008","article-title":"Public, private and non-specific antibodies induced by non-cytopathic viral infections","volume":"7","author":"Recher","year":"2004","journal-title":"Curr. Opin. Microbiol."},{"key":"2023072600444986500_bib36","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1038\/nm1670","article-title":"Extralymphatic virus sanctuaries as a consequence of potent T-cell activation","volume":"13","author":"Recher","year":"2007","journal-title":"Nat. Med."},{"key":"2023072600444986500_bib37","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ni.1715","article-title":"Cytokine-secreting follicular T cells shape the antibody repertoire","volume":"10","author":"Reinhardt","year":"2009","journal-title":"Nat. Immunol."},{"key":"2023072600444986500_bib38","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1084\/jem.20061937","article-title":"Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection","volume":"204","author":"Shin","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib39","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.4049\/jimmunol.157.7.3074","article-title":"Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice","volume":"157","author":"Thomsen","year":"1996","journal-title":"J. Immunol."},{"key":"2023072600444986500_bib40","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/S1074-7613(00)80055-2","article-title":"Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition","volume":"10","author":"Viret","year":"1999","journal-title":"Immunity."},{"key":"2023072600444986500_bib41","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1002\/1521-4141(200002)30:2&lt;560::AID-IMMU560&gt;3.0.CO;2-T","article-title":"CXCR5-deficient mice develop functional germinal centers in the splenic T cell zone","volume":"30","author":"Voigt","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"2023072600444986500_bib42","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":"2023072600444986500_bib43","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":"2023072600444986500_bib44","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1126\/science.1175194","article-title":"A vital role for interleukin-21 in the control of a chronic viral infection","volume":"324","author":"Yi","year":"2009","journal-title":"Science."},{"key":"2023072600444986500_bib45","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.immuni.2009.07.002","article-title":"The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment","volume":"31","author":"Yu","year":"2009","journal-title":"Immunity."},{"key":"2023072600444986500_bib46","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":"2023072600444986500_bib47","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1084\/jem.20090303","article-title":"T follicular helper cells differentiate from Th2 cells in response to helminth antigens","volume":"206","author":"Zaretsky","year":"2009","journal-title":"J. Exp. Med."},{"key":"2023072600444986500_bib48","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1084\/jem.20091777","article-title":"IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism","volume":"207","author":"Zotos","year":"2010","journal-title":"J. Exp. Med."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/208\/5\/987\/1742817\/jem_20101773.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/208\/5\/987\/1742817\/jem_20101773.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T20:45:43Z","timestamp":1690317943000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/208\/5\/987\/41209\/Viral-persistence-redirects-CD4-T-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,2]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,5,9]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20101773","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.10523957.13277054","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.10523957.11941054","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.10523957.11368054","asserted-by":"object"}]},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2011,5,2]]}}}