{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T06:46:17Z","timestamp":1768545977261,"version":"3.49.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T00:00:00Z","timestamp":1389225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0085882","type":"journal-article","created":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T21:52:47Z","timestamp":1389304367000},"page":"e85882","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interleukin-21 Is a Critical Regulator of CD4 and CD8 T Cell Survival during Priming under Interleukin-2 Deprivation Conditions"],"prefix":"10.1371","volume":"9","author":[{"given":"Mithun","family":"Khattar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Miyahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul M.","family":"Schroder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aini","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislaw M.","family":"Stepkowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2014,1,9]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/01.tp.0000228903.03118.be","article-title":"Janus tyrosine kinases and signal transducers and activators of transcription regulate critical functions of T cells in allograft rejection and transplantation tolerance","volume":"82","author":"SM Stepkowski","year":"2006","journal-title":"Transplantation"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.4049\/jimmunol.176.1.128","article-title":"Allograft rejection requires STAT5a\/b-regulated antiapoptotic activity in T cells but not B cells","volume":"176","author":"Y Zhang","year":"2006","journal-title":"J Immunol"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/370151a0","article-title":"Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2","volume":"370","author":"JA Johnston","year":"1994","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.immunol.26.021607.090357","article-title":"The biology of interleukin-2","volume":"26","author":"TR Malek","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2013.01.004","article-title":"Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy","volume":"38","author":"W Liao","year":"2013","journal-title":"Immunity"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Kim HP, Kelly J, Leonard WJ (2001) The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15: 159\u2013172. S1074-7613(01)00167-4 [pii].","DOI":"10.1016\/S1074-7613(01)00167-4"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.immuni.2010.08.004","article-title":"Interleukin-2 receptor signaling: at the interface between tolerance and immunity","volume":"33","author":"TR Malek","year":"2010","journal-title":"Immunity"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Gong D, Malek TR (2007) Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J Immunol 178: 242\u2013252. 178\/1\/242 [pii].","DOI":"10.4049\/jimmunol.178.1.242"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1084\/jem.20051044","article-title":"IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508","volume":"202","author":"ES Hwang","year":"2005","journal-title":"J Exp Med"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1084\/jem.20080526","article-title":"Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival","volume":"205","author":"GA Martins","year":"2008","journal-title":"J Exp Med"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.immuni.2008.04.016","article-title":"Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation","volume":"28","author":"M Shi","year":"2008","journal-title":"Immunity"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/ni.1656","article-title":"Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression","volume":"9","author":"W Liao","year":"2008","journal-title":"Nat Immunol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.immuni.2007.02.009","article-title":"Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation","volume":"26","author":"A Laurence","year":"2007","journal-title":"Immunity"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/ni.1995","article-title":"Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5","volume":"12","author":"XP Yang","year":"2011","journal-title":"Nat Immunol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.immuni.2012.02.012","article-title":"Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation","volume":"36","author":"A Ballesteros-Tato","year":"2012","journal-title":"Immunity"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1084\/jem.20111174","article-title":"STAT5 is a potent negative regulator of TFH cell differentiation","volume":"209","author":"RJ Johnston","year":"2012","journal-title":"J Exp Med"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/nm1585","article-title":"TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27\/STAT1","volume":"13","author":"A Amadi-Obi","year":"2007","journal-title":"Nat Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.immuni.2009.11.012","article-title":"Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells","volume":"32","author":"ME Pipkin","year":"2010","journal-title":"Immunity"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.4049\/jimmunol.1202067","article-title":"Transient enhanced IL-2R signaling early during priming rapidly amplifies development of functional CD8+ T effector-memory cells","volume":"189","author":"I Castro","year":"2012","journal-title":"J Immunol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"4236","DOI":"10.4049\/jimmunol.175.7.4236","article-title":"The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities","volume":"175","author":"SM Stepkowski","year":"2005","journal-title":"J Immunol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1126\/science.1087061","article-title":"Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor","volume":"302","author":"PS Changelian","year":"2003","journal-title":"Science"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1097\/01.TP.0000157117.30290.6F","article-title":"Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates","volume":"79","author":"DC Borie","year":"2005","journal-title":"Transplantation"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1097\/TP.0b013e3181b9ced7","article-title":"Monitoring of the immunomodulatory effect of CP-690,550 by analysis of the JAK\/STAT pathway in kidney transplant patients","volume":"88","author":"ME Quaedackers","year":"2009","journal-title":"Transplantation"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1517\/14712598.2010.485187","article-title":"Interleukin-2 receptor blockade with humanized monoclonal antibody for solid organ transplantation","volume":"10","author":"M Campara","year":"2010","journal-title":"Expert Opin Biol Ther"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1177\/1756285609337992","article-title":"Long-term daclizumab therapy in relapsing-remitting multiple sclerosis","volume":"2","author":"MA Rojas","year":"2009","journal-title":"Ther Adv Neurol Disord"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases","volume":"155","author":"S Sakaguchi","year":"1995","journal-title":"J Immunol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.4049\/jimmunol.1200751","article-title":"A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells","volume":"190","author":"Z Guo","year":"2013","journal-title":"J Immunol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.imlet.2010.06.001","article-title":"IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4+CD25+ regulatory T cell which jointly restrain CD4+","volume":"132","author":"G Wang","year":"2010","journal-title":"Immunol Lett"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, <etal>et al<\/etal>.. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75: 253\u2013261. 0092-8674(93)80067-O [pii].","DOI":"10.1016\/0092-8674(93)80067-O"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1126\/science.7770771","article-title":"Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta","volume":"268","author":"H Suzuki","year":"1995","journal-title":"Science"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Malek TR, Yu A, Vincek V, Scibelli P, Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17: 167\u2013178. S1074761302003679 [pii].","DOI":"10.1016\/S1074-7613(02)00367-9"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"236","DOI":"10.4049\/jimmunol.170.1.236","article-title":"Efficient induction of primary and secondary T cell-dependent immune responses in vivo in the absence of functional IL-2 and IL-15 receptors","volume":"170","author":"A Yu","year":"2003","journal-title":"J Immunol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev.immunol.26.021607.090316","article-title":"Interleukin-21: basic biology and implications for cancer and autoimmunity","volume":"26","author":"R Spolski","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/35040504","article-title":"Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function","volume":"408","author":"J Parrish-Novak","year":"2000","journal-title":"Nature"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1126\/science.1174182","article-title":"IL-21 is required to control chronic viral infection","volume":"324","author":"H Elsaesser","year":"2009","journal-title":"Science"},{"key":"ref36","doi-asserted-by":"crossref","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":"JS Yi","year":"2009","journal-title":"Science"},{"key":"ref37","doi-asserted-by":"crossref","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":"A Frohlich","year":"2009","journal-title":"Science"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"14028","DOI":"10.1073\/pnas.0804358105","article-title":"IL-21 signaling is critical for the development of type I diabetes in the NOD mouse","volume":"105","author":"R Spolski","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.2337\/db08-0882","article-title":"Interleukin-21 is required for the development of type 1 diabetes in NOD mice","volume":"58","author":"AP Sutherland","year":"2009","journal-title":"Diabetes"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.immuni.2011.01.021","article-title":"A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity","volume":"34","author":"HM McGuire","year":"2011","journal-title":"Immunity"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Davidson TS, DiPaolo RJ, Andersson J, Shevach EM (2007) Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 178: 4022\u20134026. 178\/7\/4022 [pii].","DOI":"10.4049\/jimmunol.178.7.4022"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.4049\/jimmunol.137.10.3354","article-title":"Alterations in the amino-terminal third of mouse interleukin 2: effects on biological activity and immunoreactivity","volume":"137","author":"SM Zurawski","year":"1986","journal-title":"J Immunol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1006\/bbrc.2002.6382","article-title":"Analysis of early apoptotic events in individual cells by fluorescence intensity and polarization measurements","volume":"290","author":"N Zurgil","year":"2002","journal-title":"Biochem Biophys Res Commun"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/sj.cdd.4401212","article-title":"Activation-associated mitochondrial hyperpolarization hijacks T cells toward an apoptosis-sensitized phenotype","volume":"10","author":"P Matarrese","year":"2003","journal-title":"Cell Death Differ"},{"key":"ref45","first-page":"175","article-title":"Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice","volume":"166","author":"A Strasser","year":"1990","journal-title":"Curr Top Microbiol Immunol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1126\/science.1122927","article-title":"Selective stimulation of T cell subsets with antibody-cytokine immune complexes","volume":"311","author":"O Boyman","year":"2006","journal-title":"Science"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"552","DOI":"10.2337\/diab.33.6.552","article-title":"Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus","volume":"33","author":"KS Zier","year":"1984","journal-title":"Diabetes"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1086\/429843","article-title":"Localization of a type 1 diabetes locus in the IL2RA\/CD25 region by use of tag single-nucleotide polymorphisms","volume":"76","author":"A Vella","year":"2005","journal-title":"Am J Hum Genet"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/ng1958","article-title":"Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity","volume":"39","author":"J Yamanouchi","year":"2007","journal-title":"Nat Genet"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.4049\/jimmunol.1003099","article-title":"Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes","volume":"186","author":"SA McClymont","year":"2011","journal-title":"J Immunol"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1084\/jem.20100209","article-title":"IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells","volume":"207","author":"Y Grinberg-Bleyer","year":"2010","journal-title":"J Exp Med"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1126\/science.1176487","article-title":"Immunology. A chronic need for IL-21","volume":"324","author":"LD Johnson","year":"2009","journal-title":"Science"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nm.3109","article-title":"Inadequate T follicular cell help impairs B cell immunity during HIV infection","volume":"19","author":"RA Cubas","year":"2013","journal-title":"Nat Med"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1084\/jem.20121932","article-title":"Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production","volume":"210","author":"M Perreau","year":"2013","journal-title":"J Exp Med"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2337\/db10-1157","article-title":"Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models","volume":"60","author":"HM McGuire","year":"2011","journal-title":"Diabetes"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.2337\/db11-0880","article-title":"IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response","volume":"60","author":"A Petrelli","year":"2011","journal-title":"Diabetes"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0085882","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T18:18:36Z","timestamp":1688926716000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0085882"}},"subtitle":[],"editor":[{"given":"Lionel G.","family":"Filion","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,1,9]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0085882","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,9]]}}}