{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:58:28Z","timestamp":1790391508845,"version":"4.1.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T00:00:00Z","timestamp":1421280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"DOI":"10.1371\/journal.ppat.1004517","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T21:40:30Z","timestamp":1421358030000},"page":"e1004517","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["GITR Intrinsically Sustains Early Type 1 and Late Follicular Helper CD4 T Cell Accumulation to Control a Chronic Viral Infection"],"prefix":"10.1371","volume":"11","author":[{"given":"Derek L.","family":"Clouthier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela C.","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Wortzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Luft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A.","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania H.","family":"Watts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,1,15]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.chom.2013.05.014","article-title":"Networking at the level of host immunity: immune cell interactions during persistent viral infections","volume":"13","author":"CT Ng","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"131","author":"EJ Wherry","year":"2011","journal-title":"Nature Immunology"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","article-title":"Redefining chronic viral infection","volume":"138","author":"HW Virgin","year":"2009","journal-title":"Cell"},{"key":"ref4","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":"ref5","doi-asserted-by":"crossref","first-page":"14733","DOI":"10.1073\/pnas.1009731107","article-title":"Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection","volume":"107","author":"HT Jin","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref6","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":"ref7","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/nm1492","article-title":"Interleukin-10 determines viral clearance or persistence in vivo","volume":"12","author":"DG Brooks","year":"2006","journal-title":"Nat Med"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1084\/jem.20110675","article-title":"Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection","volume":"209","author":"C Wang","year":"2012","journal-title":"J Exp Med"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"e1002913","DOI":"10.1371\/journal.ppat.1002913","article-title":"OX40 facilitates control of a persistent virus infection","volume":"8","author":"T Boettler","year":"2012","journal-title":"PLoS Pathog"},{"key":"ref10","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":"ref11","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":"M Matloubian","year":"1994","journal-title":"J Virol"},{"key":"ref12","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":"ref13","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":"M Battegay","year":"1994","journal-title":"J Virol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-pathol-011110-130254","article-title":"Pathogenic mechanisms of HIV disease","volume":"6","author":"S Moir","year":"2011","journal-title":"Annu Rev Pathol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S1074-7613(01)00236-9","article-title":"Constitutive CD27\/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion","volume":"15","author":"R Arens","year":"2001","journal-title":"Immunity"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1097\/00002030-200105250-00003","article-title":"Loss of memory (CD27) B lymphocytes in HIV-1 infection","volume":"15","author":"A De Milito","year":"2001","journal-title":"AIDS"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1084\/jem.20060651","article-title":"Elimination of chronic viral infection by blocking CD27 signaling","volume":"203","author":"M Matter","year":"2006","journal-title":"J Exp Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ni869","article-title":"Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions","volume":"4","author":"K Tesselaar","year":"2003","journal-title":"Nat Immunol"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.cytogfr.2013.12.003","article-title":"Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection","volume":"25","author":"DL Clouthier","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"5008","DOI":"10.4049\/jimmunol.173.8.5008","article-title":"Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells","volume":"173","author":"GL Stephens","year":"2004","journal-title":"J Immunol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"7490","DOI":"10.4049\/jimmunol.0802751","article-title":"GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo","volume":"182","author":"RW van Olffen","year":"2009","journal-title":"J Immunol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nri1867","article-title":"The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity?","volume":"6","author":"EM Shevach","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1002\/eji.201343451","article-title":"Modulation of Treg cells\/T effector function by GITR signaling is context-dependent","volume":"43","author":"A Ephrem","year":"2013","journal-title":"Eur J Immunol"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1182\/blood-2001-12-0276","article-title":"Role of GITR in activation response of T lymphocytes","volume":"100","author":"S Ronchetti","year":"2002","journal-title":"Blood"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1084\/jem.167.5.1719","article-title":"Organ-specific selection of viral variants during chronic infection","volume":"167","author":"R Ahmed","year":"1988","journal-title":"J Exp Med"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"7223","DOI":"10.4049\/jimmunol.1001912","article-title":"CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection","volume":"185","author":"LM Snell","year":"2010","journal-title":"J Immunol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"H Pircher","year":"1989","journal-title":"Nature"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nm866","article-title":"Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo","volume":"9","author":"JN Blattman","year":"2003","journal-title":"Nat Med"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1172\/JCI67008","article-title":"PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells","volume":"123","author":"EE West","year":"2013","journal-title":"J Clin Invest"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1002\/eji.200637023","article-title":"Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections","volume":"37","author":"MF Bachmann","year":"2007","journal-title":"Eur J Immunol"},{"key":"ref31","doi-asserted-by":"crossref","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":"EJ Wherry","year":"2003","journal-title":"J Virol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1084\/jem.20101773","article-title":"Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells","volume":"208","author":"LM Fahey","year":"2011","journal-title":"J Exp Med"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"S Crotty","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/(SICI)1521-4141(199801)28:01<390::AID-IMMU390>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":"A Oxenius","year":"1998","journal-title":"Eur J Immunol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ follicular regulatory T cells control the germinal center response","volume":"17","author":"MA Linterman","year":"2011","journal-title":"Nat Med"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/nm.2426","article-title":"Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions","volume":"17","author":"Y Chung","year":"2011","journal-title":"Nat Med"},{"key":"ref37","first-page":"139","article-title":"Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules","volume":"4","author":"T So","year":"2013","journal-title":"Front Immunol"},{"key":"ref38","first-page":"245","article-title":"The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function","volume":"3","author":"JM Han","year":"2012","journal-title":"Front Immunol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1128\/MCB.20.8.2687-2695.2000","article-title":"The Rel\/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L)","volume":"20","author":"C Chen","year":"2000","journal-title":"Mol Cell Biol"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nri3198","article-title":"Regulation and function of mTOR signalling in T cell fate decisions","volume":"12","author":"H Chi","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"7869","DOI":"10.4049\/jimmunol.174.12.7869","article-title":"Glucocorticoid-induced TNF receptor functions as a costimulatory receptor that promotes survival in early phases of T cell activation","volume":"174","author":"EM Esparza","year":"2005","journal-title":"J Immunol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"7306","DOI":"10.4049\/jimmunol.172.12.7306","article-title":"Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells","volume":"172","author":"F Kanamaru","year":"2004","journal-title":"J Immunol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.4049\/jimmunol.179.9.5916","article-title":"Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells","volume":"179","author":"S Ronchetti","year":"2007","journal-title":"J Immunol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.4049\/jimmunol.1003156","article-title":"OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling","volume":"186","author":"T So","year":"2011","journal-title":"J Immunol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nri3152","article-title":"Expanding roles for CD4(+) T cells in immunity to viruses","volume":"12","author":"SL Swain","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"ref46","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.1401002","article-title":"Anti-GITR agonist therapy intrinsically enhances CD8 T cell responses to chronic LCMV thereby circumventing LCMV-induced downregulation of co-stimulatory GITRL on APC","volume":"193","author":"DL Clouthier","year":"2014","journal-title":"J Immunol"},{"key":"ref47","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":"ref48","doi-asserted-by":"crossref","first-page":"e31632","DOI":"10.1371\/journal.pone.0031632","article-title":"Murine B cell development and antibody responses to model antigens are not impaired in the absence of the TNF receptor GITR","volume":"7","author":"LS Teodorovic","year":"2012","journal-title":"PLoS One"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1084\/jem.20061852","article-title":"Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease","volume":"204","author":"K Lahl","year":"2007","journal-title":"J Exp Med"},{"issue":"19","key":"ref50","first-page":"10","article-title":"Animal models using lymphocytic choriomeningitis virus","volume":"19","author":"M von Herrath","year":"2001","journal-title":"Curr Protoc Immunol"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.ppat.1004517","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,29]],"date-time":"2020-08-29T01:32:39Z","timestamp":1598664759000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1004517"}},"subtitle":[],"editor":[{"given":"Christopher M.","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,1,15]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,1,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1004517","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,15]]}}}