{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:16:57Z","timestamp":1792603017547,"version":"4.5.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2011,5,29]],"date-time":"2011-05-29T00:00:00Z","timestamp":1306627200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2011,7]]},"DOI":"10.1038\/ni.2046","type":"journal-article","created":{"date-parts":[[2011,5,29]],"date-time":"2011-05-29T14:27:47Z","timestamp":1306679267000},"page":"663-671","source":"Crossref","is-referenced-by-count":471,"title":["Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection"],"prefix":"10.1038","volume":"12","author":[{"given":"Charlly","family":"Kao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J","family":"Oestreich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Paley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill M","family":"Angelosanto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed-Alkhatim A","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Intlekofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M","family":"Boss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L","family":"Reiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S","family":"Weinmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E John","family":"Wherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,5,29]]},"reference":[{"key":"BFni2046_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1146\/annurev.immunol.25.022106.141548","volume":"25","author":"MA Williams","year":"2007","unstructured":"Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171\u2013192 (2007).","journal-title":"Annu. Rev. Immunol."},{"key":"BFni2046_CR2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","volume":"138","author":"HW Virgin","year":"2009","unstructured":"Virgin, H.W., Wherry, E.J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30\u201350 (2009).","journal-title":"Cell"},{"key":"BFni2046_CR3","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","volume":"439","author":"DL Barber","year":"2006","unstructured":"Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682\u2013687 (2006).","journal-title":"Nature"},{"key":"BFni2046_CR4","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","volume":"27","author":"EJ Wherry","year":"2007","unstructured":"Wherry, E.J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670\u2013684 (2007).","journal-title":"Immunity"},{"key":"BFni2046_CR5","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1084\/jem.20100637","volume":"207","author":"J Fourcade","year":"2010","unstructured":"Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175\u20132186 (2010).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR6","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1084\/jem.20100643","volume":"27","author":"K Sakuishi","year":"2010","unstructured":"Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 27, 2187\u20132194 (2010).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR7","doi-asserted-by":"publisher","first-page":"3167","DOI":"10.1200\/JCO.2009.26.7609","volume":"28","author":"JR Brahmer","year":"2010","unstructured":"Brahmer, J.R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167\u20133175 (2010).","journal-title":"J. Clin. Oncol."},{"key":"BFni2046_CR8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ni.1679","volume":"10","author":"SD Blackburn","year":"2009","unstructured":"Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29\u201337 (2009).","journal-title":"Nat. Immunol."},{"key":"BFni2046_CR9","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1084\/jem.20081398","volume":"205","author":"RB Jones","year":"2008","unstructured":"Jones, R.B. et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205, 2763\u20132779 (2008).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR10","doi-asserted-by":"publisher","first-page":"14733","DOI":"10.1073\/pnas.1009731107","volume":"107","author":"HT Jin","year":"2010","unstructured":"Jin, H.T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 107, 14733\u201314738 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2046_CR11","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1002\/eji.201040340","volume":"40","author":"B Vali","year":"2010","unstructured":"Vali, B. et al. HCV-specific T cells in HCV\/HIV co-infection show elevated frequencies of dual Tim-3\/PD-1 expression that correlate with liver disease progression. Eur. J. Immunol. 40, 2493\u20132505 (2010).","journal-title":"Eur. J. Immunol."},{"key":"BFni2046_CR12","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.immuni.2009.06.019","volume":"31","author":"H Shin","year":"2009","unstructured":"Shin, H. et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309\u2013320 (2009).","journal-title":"Immunity"},{"key":"BFni2046_CR13","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.immuni.2009.06.021","volume":"31","author":"A Kallies","year":"2009","unstructured":"Kallies, A., Xin, A., Belz, G.T. & Nutt, S.L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283\u2013295 (2009).","journal-title":"Immunity"},{"key":"BFni2046_CR14","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.immuni.2009.05.014","volume":"31","author":"RL Rutishauser","year":"2009","unstructured":"Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296\u2013308 (2009).","journal-title":"Immunity"},{"key":"BFni2046_CR15","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.immuni.2007.07.010","volume":"27","author":"NS Joshi","year":"2007","unstructured":"Joshi, N.S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281\u2013295 (2007).","journal-title":"Immunity"},{"key":"BFni2046_CR16","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1084\/jem.20070841","volume":"204","author":"AM Intlekofer","year":"2007","unstructured":"Intlekofer, A.M. et al. Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J. Exp. Med. 204, 2015\u20132021 (2007).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR17","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1126\/science.1159806","volume":"321","author":"AM Intlekofer","year":"2008","unstructured":"Intlekofer, A.M. et al. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321, 408\u2013411 (2008).","journal-title":"Science"},{"key":"BFni2046_CR18","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.immuni.2009.03.013","volume":"30","author":"EG Schulz","year":"2009","unstructured":"Schulz, E.G., Mariani, L., Radbruch, A. & Hofer, T. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-\u03b3 and interleukin-12. Immunity 30, 673\u2013683 (2009).","journal-title":"Immunity"},{"key":"BFni2046_CR19","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1084\/jem.20061937","volume":"204","author":"H Shin","year":"2007","unstructured":"Shin, H., Blackburn, S.D., Blattman, J.N. & Wherry, E.J. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941\u2013949 (2007).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR20","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1002\/eji.200939842","volume":"40","author":"AC Anderson","year":"2010","unstructured":"Anderson, A.C. et al. T-bet, a Th1 transcription factor regulates the expression of Tim-3. Eur. J. Immunol. 40, 859\u2013866 (2010).","journal-title":"Eur. J. Immunol."},{"key":"BFni2046_CR21","doi-asserted-by":"publisher","first-page":"4832","DOI":"10.4049\/jimmunol.181.7.4832","volume":"181","author":"KJ Oestreich","year":"2008","unstructured":"Oestreich, K.J., Yoon, H., Ahmed, R. & Boss, J.M. NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181, 4832\u20134839 (2008).","journal-title":"J. Immunol."},{"key":"BFni2046_CR22","doi-asserted-by":"publisher","first-page":"11992","DOI":"10.1074\/jbc.M513613200","volume":"281","author":"KM Beima","year":"2006","unstructured":"Beima, K.M. et al. T-bet binding to newly identified target gene promoters is cell type-independent but results in variable context-dependent functional effects. J. Biol. Chem. 281, 11992\u201312000 (2006).","journal-title":"J. Biol. Chem."},{"key":"BFni2046_CR23","doi-asserted-by":"publisher","first-page":"2980","DOI":"10.1101\/gad.1689708","volume":"22","author":"SA Miller","year":"2008","unstructured":"Miller, S.A., Huang, A.C., Miazgowicz, M.M., Brassil, M.M. & Weinmann, A.S. Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev. 22, 2980\u20132993 (2008).","journal-title":"Genes Dev."},{"key":"BFni2046_CR24","doi-asserted-by":"publisher","first-page":"2016","DOI":"10.1073\/pnas.0409512102","volume":"102","author":"DS Mehta","year":"2005","unstructured":"Mehta, D.S., Wurster, A.L., Weinmann, A.S. & Grusby, M.J. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl. Acad. Sci. USA 102, 2016\u20132021 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2046_CR25","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/ni.1837","volume":"11","author":"S Crotty","year":"2010","unstructured":"Crotty, S., Johnston, R.J. & Schoenberger, S.P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114\u2013120 (2010).","journal-title":"Nat. Immunol."},{"key":"BFni2046_CR26","doi-asserted-by":"publisher","first-page":"17876","DOI":"10.1073\/pnas.0909357106","volume":"106","author":"RG Jenner","year":"2009","unstructured":"Jenner, R.G. et al. The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc. Natl. Acad. Sci. USA 106, 17876\u201317881 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2046_CR27","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.4049\/jimmunol.0900182","volume":"183","author":"C Petrovas","year":"2009","unstructured":"Petrovas, C. et al. Differential association of programmed death-1 and CD57 with ex vivo survival of CD8+ T cells in HIV infection. J. Immunol. 183, 1120\u20131132 (2009).","journal-title":"J. Immunol."},{"key":"BFni2046_CR28","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature05115","volume":"443","author":"CL Day","year":"2006","unstructured":"Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350\u2013354 (2006).","journal-title":"Nature"},{"key":"BFni2046_CR29","doi-asserted-by":"publisher","first-page":"3266","DOI":"10.4049\/jimmunol.177.5.3266","volume":"177","author":"J Louten","year":"2006","unstructured":"Louten, J., van Rooijen, N. & Biron, C.A. Type 1 IFN deficiency in the absence of normal splenic architecture during lymphocytic choriomeningitis virus infection. J. Immunol. 177, 3266\u20133272 (2006).","journal-title":"J. Immunol."},{"key":"BFni2046_CR30","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.4049\/jimmunol.1000841","volume":"185","author":"KJ Mackerness","year":"2010","unstructured":"Mackerness, K.J. et al. Pronounced virus-dependent activation drives exhaustion but sustains IFN-\u03b3 transcript levels. J. Immunol. 185, 3643\u20133651 (2010).","journal-title":"J. Immunol."},{"key":"BFni2046_CR31","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/ni794","volume":"3","author":"M Afkarian","year":"2002","unstructured":"Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat. Immunol. 3, 549\u2013557 (2002).","journal-title":"Nat. Immunol."},{"key":"BFni2046_CR32","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1126\/science.1074900","volume":"297","author":"KB Nguyen","year":"2002","unstructured":"Nguyen, K.B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-\u03b3 response to viral infection. Science 297, 2063\u20132066 (2002).","journal-title":"Science"},{"key":"BFni2046_CR33","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1089\/10799900360708632","volume":"23","author":"L Hibbert","year":"2003","unstructured":"Hibbert, L., Pflanz, S., De Waal Malefyt, R. & Kastelein, R.A. IL-27 and IFN-\u03b1 signal via Stat1 and Stat3 and induce T-bet and IL-12R\u03b22 in naive T cells. J. Interferon Cytokine Res. 23, 513\u2013522 (2003).","journal-title":"J. Interferon Cytokine Res."},{"key":"BFni2046_CR34","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ni1268","volume":"6","author":"AM Intlekofer","year":"2005","unstructured":"Intlekofer, A.M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236\u20131244 (2005).","journal-title":"Nat. Immunol."},{"key":"BFni2046_CR35","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1084\/jem.160.2.521","volume":"160","author":"R Ahmed","year":"1984","unstructured":"Ahmed, R., Salmi, A., Butler, L.D., Chiller, J.M. & Oldstone, M.B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521\u2013540 (1984).","journal-title":"J. Exp. Med."},{"key":"BFni2046_CR36","doi-asserted-by":"publisher","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","volume":"77","author":"EJ Wherry","year":"2003","unstructured":"Wherry, E.J., Blattman, J.N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911\u20134927 (2003).","journal-title":"J. Virol."},{"key":"BFni2046_CR37","doi-asserted-by":"publisher","first-page":"4928","DOI":"10.1128\/JVI.02632-06","volume":"81","author":"MF Kotturi","year":"2007","unstructured":"Kotturi, M.F. et al. The CD8+ T-cell response to lymphocytic choriomeningitis virus involves the L antigen: uncovering new tricks for an old virus. J. Virol. 81, 4928\u20134940 (2007).","journal-title":"J. Virol."},{"key":"BFni2046_CR38","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1126\/science.1059835","volume":"292","author":"AC Mullen","year":"2001","unstructured":"Mullen, A.C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907\u20131910 (2001).","journal-title":"Science"},{"key":"BFni2046_CR39","doi-asserted-by":"publisher","first-page":"8392","DOI":"10.1073\/pnas.90.18.8392","volume":"90","author":"WS Pear","year":"1993","unstructured":"Pear, W.S., Nolan, G.P., Scott, M.L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl. Acad. Sci. USA 90, 8392\u20138396 (1993).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2046_CR40","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1084\/jem.20081242","volume":"206","author":"F Cruz-Guilloty","year":"2009","unstructured":"Cruz-Guilloty, F. et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J. Exp. Med. 206, 51\u201359 (2009).","journal-title":"J. Exp. Med."}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/ni.2046.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ni.2046","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ni.2046.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T19:37:58Z","timestamp":1684438678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ni.2046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,29]]},"references-count":40,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2011,7]]}},"alternative-id":["BFni2046"],"URL":"https:\/\/doi.org\/10.1038\/ni.2046","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.12093959.13604054","asserted-by":"object"}]},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,29]]}}}