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In the current study, we examined the role of IL-2 in IFN-\u03b3 production by CD8+ immune T cells in their secondary responses using T. gondii\u2013specific CD8+ T cell hybridomas and splenic CD8+ immune T cells from chronically infected mice. The majority (92%) of CD8+ T cell hybridomas produced large amounts of IFN-\u03b3 only when a low amount (0.5 ng\/ml) of exogenous IL-2 was provided in combination with T. gondii Ags. Inhibition of cell proliferation by mitomycin C did not affect the enhancing effect of IL-2 on the IFN-\u03b3 production, and significant increases in transcription factor T-bet expression were associated with the IL-2\u2013mediated IFN-\u03b3 amplification. Splenic CD8+ immune T cells produced similar low levels of IL-2 in the secondary response to T. gondii, and a blocking of IL-2 signaling by anti\u2013IL-2R\u03b1 Ab or inhibitors of JAK1 and JAK3 significantly reduced IFN-\u03b3 production of the T cells. This IL-2\u2013mediated upregulation of IFN-\u03b3 production was observed in mitomycin C\u2013treated CD8+ immune T cells, thus independent from their cell division. Therefore, endogenous IL-2 produced by CD8+ immune T cells can play an important autocrine-enhancing role on their IFN-\u03b3 production in the secondary responses to T. gondii, suggesting an importance of induction of CD8+ immune T cells with an appropriate IL-2 production for vaccine development.<\/jats:p>","DOI":"10.4049\/jimmunol.1202256","type":"journal-article","created":{"date-parts":[[2013,1,29]],"date-time":"2013-01-29T01:37:24Z","timestamp":1359423444000},"page":"2199-2207","source":"Crossref","is-referenced-by-count":40,"title":["IL-2 Produced by CD8+ Immune T Cells Can Augment Their IFN-\u03b3 Production Independently from Their Proliferation in the Secondary Response to an Intracellular Pathogen"],"prefix":"10.1093","volume":"190","author":[{"given":"Qila","family":"Sa","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerold","family":"Woodward","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,3,1]]},"reference":[{"key":"2025032406390289700_r1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.immunol.21.120601.141114","article-title":"CD8 T cell responses to infectious pathogens","volume":"21","author":"Wong","year":"2003","journal-title":"Annu. 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Immunol."},{"key":"2025032406390289700_r3","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.immuni.2011.07.010","article-title":"CD8(+) T cells: foot soldiers of the immune system","volume":"35","author":"Zhang","year":"2011","journal-title":"Immunity"},{"key":"2025032406390289700_r4","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/nature04790","article-title":"Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells","volume":"441","author":"Williams","year":"2006","journal-title":"Nature"},{"key":"2025032406390289700_r5","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":"Bachmann","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025032406390289700_r6","doi-asserted-by":"crossref","first-page":"6719","DOI":"10.4049\/jimmunol.0904089","article-title":"Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8+ effector and memory T cells","volume":"184","author":"Mitchell","year":"2010","journal-title":"J. Immunol."},{"key":"2025032406390289700_r7","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":"Pipkin","year":"2010","journal-title":"Immunity"},{"key":"2025032406390289700_r8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1126\/science.272.5258.54","article-title":"Immunological memory and protective immunity: understanding their relation","volume":"272","author":"Ahmed","year":"1996","journal-title":"Science"},{"key":"2025032406390289700_r9","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1038\/369652a0","article-title":"Virus-specific CD8+ T-cell memory determined by clonal burst size","volume":"369","author":"Hou","year":"1994","journal-title":"Nature"},{"key":"2025032406390289700_r10","doi-asserted-by":"crossref","first-page":"14017","DOI":"10.1073\/pnas.0805452105","article-title":"Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria","volume":"105","author":"Schmidt","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406390289700_r11","first-page":"2090","volume-title":"Toxoplasma gondii.","author":"McCabe","year":"1990"},{"key":"2025032406390289700_r12","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/S0171-2985(99)80064-3","article-title":"Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function","volume":"201","author":"Yap","year":"1999","journal-title":"Immunobiology"},{"key":"2025032406390289700_r13","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1017\/S1462399411002018","article-title":"Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain","volume":"13","author":"Suzuki","year":"2011","journal-title":"Expert Rev. Mol. Med."},{"key":"2025032406390289700_r14","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1126\/science.3128869","article-title":"Interferon-gamma: the major mediator of resistance against Toxoplasma gondii","volume":"240","author":"Suzuki","year":"1988","journal-title":"Science"},{"key":"2025032406390289700_r15","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.4049\/jimmunol.144.5.1954","article-title":"The effect of anti-IFN-gamma antibody on the protective effect of Lyt-2+ immune T cells against toxoplasmosis in mice","volume":"144","author":"Suzuki","year":"1990","journal-title":"J. Immunol."},{"key":"2025032406390289700_r16","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4049\/jimmunol.146.1.286","article-title":"Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine","volume":"146","author":"Gazzinelli","year":"1991","journal-title":"J. Immunol."},{"key":"2025032406390289700_r17","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1046\/j.1469-0691.2002.00485.x","article-title":"Toxoplasma gondii: transmission, diagnosis and prevention","volume":"8","author":"Hill","year":"2002","journal-title":"Clin. Microbiol. Infect."},{"key":"2025032406390289700_r18"},{"key":"2025032406390289700_r19","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1089\/jir.2005.25.338","article-title":"Importance of CD8(+)Vbeta8(+) T cells in IFN-gamma-mediated prevention of toxoplasmic encephalitis in genetically resistant BALB\/c mice","volume":"25","author":"Wang","year":"2005","journal-title":"J. Interferon Cytokine Res."},{"key":"2025032406390289700_r20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1600-065X.2010.00992.x","article-title":"Immunology of Toxoplasma gondii","volume":"240","author":"Munoz","year":"2011","journal-title":"Immunol. Rev."},{"key":"2025032406390289700_r21","first-page":"322","article-title":"Toxoplasmosis in the non-AIDS immunocompromised host","volume":"13","author":"Israelski","year":"1993","journal-title":"Curr. Clin. Top. Infect. Dis."},{"key":"2025032406390289700_r22","first-page":"223","volume-title":"Text Book of AIDS Medicine.","author":"Wong","year":"1994"},{"key":"2025032406390289700_r23","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.4049\/jimmunol.135.6.4160","article-title":"In vivo recombinant interleukin 2 administration enhances survival against a lethal challenge with Toxoplasma gondii","volume":"135","author":"Sharma","year":"1985","journal-title":"J. Immunol."},{"key":"2025032406390289700_r24","first-page":"107","article-title":"Effect of rIFN-gamma and IL-2 treatments in mouse and nude rat infections with Toxoplasma gondii","volume":"2","author":"Benedetto","year":"1991","journal-title":"Eur. Cytokine Netw."},{"key":"2025032406390289700_r25","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/j.1348-0421.1993.tb01680.x","article-title":"Enhancement by recombinant human interleukin 2 of host resistance to Toxoplasma gondii infection in pregnant mice","volume":"37","author":"Shirahata","year":"1993","journal-title":"Microbiol. Immunol."},{"key":"2025032406390289700_r26","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1128\/iai.61.6.2284-2288.1993","article-title":"Susceptibility to chronic infection with Toxoplasma gondii does not correlate with susceptibility to acute infection in mice","volume":"61","author":"Suzuki","year":"1993","journal-title":"Infect. 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Immunol."},{"key":"2025032406390289700_r39","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1126\/science.7973658","article-title":"Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID","volume":"266","author":"Russell","year":"1994","journal-title":"Science"},{"key":"2025032406390289700_r40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/370153a0","article-title":"Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells","volume":"370","author":"Witthuhn","year":"1994","journal-title":"Nature"},{"key":"2025032406390289700_r41","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1038\/ni0901-882","article-title":"Inducible IL-2 production by dendritic cells revealed by global gene expression analysis","volume":"2","author":"Granucci","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025032406390289700_r42","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":"Malek","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2025032406390289700_r43","doi-asserted-by":"crossref","first-page":"542","DOI":"10.4049\/jimmunol.130.2.542","article-title":"Helper cell-independent cytolytic T lymphocytes specific for a minor histocompatibility antigen","volume":"130","author":"Roopenian","year":"1983","journal-title":"J. Immunol."},{"key":"2025032406390289700_r44","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.4049\/jimmunol.142.7.2187","article-title":"Helper-independent CD8+ cytotoxic T lymphocytes express IL-1 receptors and require IL-1 for secretion of IL-2","volume":"142","author":"Klarnet","year":"1989","journal-title":"J. Immunol."},{"key":"2025032406390289700_r45","doi-asserted-by":"crossref","first-page":"e1000815","DOI":"10.1371\/journal.ppat.1000815","article-title":"Differential regulation of effector- and central-memory responses to Toxoplasma gondii infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells","volume":"6","author":"Wilson","year":"2010","journal-title":"PLoS Pathog."},{"key":"2025032406390289700_r46","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/ni.2079","article-title":"Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells","volume":"12","author":"Feau","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025032406390289700_r47","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/353858a0","article-title":"Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis","volume":"353","author":"Lenardo","year":"1991","journal-title":"Nature"},{"key":"2025032406390289700_r48","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.4049\/jimmunol.140.11.3943","article-title":"Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt-1+, L3T4+ T cells in mice","volume":"140","author":"Suzuki","year":"1988","journal-title":"J. Immunol."},{"key":"2025032406390289700_r49","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1365-2249.1991.tb08150.x","article-title":"CD8+ T cells are the major lymphocyte subpopulation involved in the protective immune response to Toxoplasma gondii in mice","volume":"84","author":"Parker","year":"1991","journal-title":"Clin. Exp. Immunol."},{"key":"2025032406390289700_r50","doi-asserted-by":"crossref","first-page":"175","DOI":"10.4049\/jimmunol.149.1.175","article-title":"Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii","volume":"149","author":"Gazzinelli","year":"1992","journal-title":"J. Immunol."},{"key":"2025032406390289700_r51","doi-asserted-by":"crossref","first-page":"5790","DOI":"10.1128\/IAI.00098-06","article-title":"Organ- and disease-stage-specific regulation of Toxoplasma gondii-specific CD8-T-cell responses by CD4 T cells","volume":"74","author":"L\u00fctjen","year":"2006","journal-title":"Infect. Immun."},{"key":"2025032406390289700_r52","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1099\/0022-1317-83-9-2123","article-title":"High numbers of IL-2-producing CD8+ T cells during viral infection: correlation with stable memory development","volume":"83","author":"Kristensen","year":"2002","journal-title":"J. Gen. Virol."},{"key":"2025032406390289700_r53","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1182\/blood-2005-12-4818","article-title":"HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells","volume":"107","author":"Betts","year":"2006","journal-title":"Blood"},{"key":"2025032406390289700_r54","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.1128\/IAI.70.9.4757-4761.2002","article-title":"Susceptibility of interleukin-2-deficient mice to Toxoplasma gondii is associated with a defect in the production of gamma interferon","volume":"70","author":"Villegas","year":"2002","journal-title":"Infect. 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