{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:53:36Z","timestamp":1792738416640,"version":"4.5.0"},"reference-count":60,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,12,21]]},"abstract":"<jats:p>We examined the regulation of virus-specific CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Our study shows that within the same persistently infected host, different mechanisms can operate to silence antiviral T cell responses; CD8 T cells specific to one dominant viral epitope were deleted, whereas CD8 T cells responding to another dominant epitope persisted indefinitely. These virus-specific CD8 T cells expressed activation markers (CD69hi, CD44hi, CD62Llo) and proliferated in vivo but were unable to elaborate any antiviral effector functions. This unresponsive phenotype was more pronounced under conditions of CD4 T cell deficiency, highlighting the importance of CD8\u2013 CD4 T cell collaboration in controlling persistent infections. Importantly, in the presence of CD4 T cell help, adequate CD8 effector activity was maintained and the chronic viral infection eventually resolved. The persistence of activated virus-specific CD8 T cells without effector function reveals a novel mechanism for silencing antiviral immune responses and also offers new possibilities for enhancing CD8 T cell immunity in chronically infected hosts.<\/jats:p>","DOI":"10.1084\/jem.188.12.2205","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"2205-2213","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1640,"title":["Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function"],"prefix":"10.1084","volume":"188","author":[{"given":"Allan J.","family":"Zajac","sequence":"first","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph N.","family":"Blattman","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaja","family":"Murali-Krishna","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.D.","family":"Sourdive","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Suresh","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Altman","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1998,12,21]]},"reference":[{"key":"2023072508040120600_B1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/369031a0","article-title":"Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice","volume":"369","author":"K\u00e4gi","year":"1994","journal-title":"Nature"},{"key":"2023072508040120600_B2","doi-asserted-by":"crossref","first-page":"10854","DOI":"10.1073\/pnas.91.23.10854","article-title":"Immune function in mice lacking the perforin gene","volume":"91","author":"Walsh","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072508040120600_B3","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1006\/viro.1995.1477","article-title":"An essential role for type 1 interferon-\u03b3 in terminating persistent viral infection","volume":"212","author":"Tishon","year":"1995","journal-title":"Virology"},{"key":"2023072508040120600_B4","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":"2023072508040120600_B5","first-page":"1","article-title":"Cytotoxic T cell effector and memory function in viral immunity","volume":"206","author":"Doherty","year":"1996","journal-title":"Curr Top Microbiol Immunol"},{"key":"2023072508040120600_B6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1074-7613(00)80295-2","article-title":"Intracellular inactivation of hepatitis B virus by cytotoxic T lymphocytes","volume":"4","author":"Guidotti","year":"1996","journal-title":"Immunity"},{"key":"2023072508040120600_B7","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1126\/science.1352912","article-title":"Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones","volume":"257","author":"Riddell","year":"1992","journal-title":"Science"},{"key":"2023072508040120600_B8","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nm0596-551","article-title":"Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes","volume":"2","author":"Heslop","year":"1996","journal-title":"Nature Med"},{"key":"2023072508040120600_B9"},{"key":"2023072508040120600_B10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev.immunol.15.1.405","article-title":"Human cytotoxic T-lymphocytes responses to Epstein-Barr virus infection","volume":"15","author":"Rickinson","year":"1997","journal-title":"Annu Rev Immunol"},{"key":"2023072508040120600_B11","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.187.9.1395","article-title":"Direct visualization of antigen-specific CD8+T cells during the primary immune response to Epstein-Barr virus in vivo","volume":"187","author":"Callan","year":"1998","journal-title":"J Exp Med"},{"key":"2023072508040120600_B12","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/370463a0","article-title":"Major expansion of CD8+ T cells with a predominant V\u03b2 usage during the primary immune response to HIV","volume":"370","author":"Pantaleo","year":"1994","journal-title":"Nature"},{"key":"2023072508040120600_B13","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1073\/pnas.94.1.254","article-title":"The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia","volume":"94","author":"Pantaleo","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072508040120600_B14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nm0195-59","article-title":"HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women","volume":"1","author":"Rowland-Jones","year":"1995","journal-title":"Nature Med"},{"key":"2023072508040120600_B15","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1084\/jem.181.4.1365","article-title":"Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics","volume":"181","author":"Klein","year":"1995","journal-title":"J Exp Med"},{"key":"2023072508040120600_B16","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0167-5699(98)01288-2","article-title":"Cytotoxic T lymphocytes in HIV-1 infection: a killing paradox","volume":"19","author":"Klein","year":"1998","journal-title":"Immunol Today"},{"key":"2023072508040120600_B17","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1126\/science.279.5359.2103","article-title":"Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA","volume":"279","author":"Ogg","year":"1998","journal-title":"Science"},{"key":"2023072508040120600_B18","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":"2023072508040120600_B19","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":"2023072508040120600_B20","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1084\/jem.184.3.863","article-title":"Progressive loss of CD8+ T cell\u2013mediated control of a \u03b3-herpesvirus in the absence of CD4+T cells","volume":"184","author":"Cardin","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508040120600_B21","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1126\/science.278.5342.1447","article-title":"Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia","volume":"278","author":"Rosenberg","year":"1997","journal-title":"Science"},{"key":"2023072508040120600_B22","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/362758a0","article-title":"Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells","volume":"362","author":"Moskophidis","year":"1993","journal-title":"Nature"},{"key":"2023072508040120600_B23","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0966-842X(93)90133-C","article-title":"Immune exhaustion: driving virus-specific CD8+ T cells to death","volume":"1","author":"Doherty","year":"1993","journal-title":"Trends Microbiol"},{"key":"2023072508040120600_B24","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1084\/jem.187.9.1383","article-title":"Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I\u2013peptide complexes","volume":"187","author":"Gallimore","year":"1998","journal-title":"J Exp Med"},{"key":"2023072508040120600_B25","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"Altman","year":"1996","journal-title":"Science"},{"key":"2023072508040120600_B26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1074-7613(00)80470-7","article-title":"Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection","volume":"8","author":"Murali-Krishna","year":"1998","journal-title":"Immunity"},{"key":"2023072508040120600_B27","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1084\/jem.187.9.1367","article-title":"A new look at T cells","volume":"187","author":"McMicheal","year":"1998","journal-title":"J Exp Med"},{"key":"2023072508040120600_B28"},{"key":"2023072508040120600_B29","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/353180a0","article-title":"Normal development and function of CD8+ cells but markedly decreased helper activity in mice lacking CD4","volume":"353","author":"Rahemtulla","year":"1991","journal-title":"Nature"},{"key":"2023072508040120600_B30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.160.2.521","article-title":"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","volume":"160","author":"Ahmed","year":"1984","journal-title":"J Exp Med"},{"key":"2023072508040120600_B31","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/369648a0","article-title":"Cytotoxic T-cell memory without antigen","volume":"369","author":"Lau","year":"1994","journal-title":"Nature"},{"key":"2023072508040120600_B32","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1084\/jem.179.4.1127","article-title":"Turnover of naive- and memory-phenotype T cells","volume":"179","author":"Tough","year":"1994","journal-title":"J Exp Med"},{"key":"2023072508040120600_B33","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1128\/jvi.62.6.2102-2106.1988","article-title":"T4+ T helper cell function in vivo: differential requirement for induction of anti-viral cytotoxic T cell and antibody responses","volume":"62","author":"Ahmed","year":"1988","journal-title":"J Virol"},{"key":"2023072508040120600_B34","doi-asserted-by":"crossref","first-page":"5611","DOI":"10.1128\/jvi.64.11.5611-5616.1990","article-title":"In vivo selection of lymphocyte-tropic and macrophage-tropic variants of lymphocytic choriomeningitis virus during persistent infection","volume":"64","author":"King","year":"1990","journal-title":"J Virol"},{"key":"2023072508040120600_B35","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.4049\/jimmunol.138.10.3120","article-title":"Distinction of virgin and memory T lymphocytes: stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation","volume":"138","author":"Budd","year":"1987","journal-title":"J Immunol"},{"key":"2023072508040120600_B36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.1996.tb00897.x","article-title":"Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8","volume":"149","author":"Cobbold","year":"1996","journal-title":"Immunol Rev"},{"key":"2023072508040120600_B37","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1600-065X.1996.tb00904.x","article-title":"Immune deviation\u2014 the third dimension of nondeletional T cell tolerance","volume":"149","author":"R\u00f6cken","year":"1996","journal-title":"Immunol Rev"},{"key":"2023072508040120600_B38","doi-asserted-by":"crossref","first-page":"5870","DOI":"10.4049\/jimmunol.154.11.5870","article-title":"Temporal loss of the activated L-selectin-low phenotype for virus-specific CD8+ memory T cells","volume":"154","author":"Tripp","year":"1995","journal-title":"J Immunol"},{"key":"2023072508040120600_B39","doi-asserted-by":"crossref","first-page":"369","DOI":"10.4049\/jimmunol.141.2.369","article-title":"Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation","volume":"141","author":"Yokoyama","year":"1988","journal-title":"J Immunol"},{"key":"2023072508040120600_B40","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.4049\/jimmunol.142.6.1854","article-title":"Leu 23 induction as an early marker of functional CD3\/T cell antigen receptor triggering: requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C","volume":"142","author":"Testi","year":"1989","journal-title":"J Immunol"},{"key":"2023072508040120600_B41","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/0167-5699(94)90193-7","article-title":"The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells","volume":"15","author":"Testi","year":"1994","journal-title":"Immunol Today"},{"key":"2023072508040120600_B42","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/313318a0","article-title":"Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester","volume":"313","author":"Truneh","year":"1985","journal-title":"Nature"},{"key":"2023072508040120600_B43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1600-065X.1987.tb00501.x","article-title":"T-lymphocyte activation: the role of protein kinase C and the bifurcating inositol phospholipid signal transduction pathway","volume":"95","author":"Isakov","year":"1987","journal-title":"Immunol Rev"},{"key":"2023072508040120600_B44","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1126\/science.1439825","article-title":"B cells turn off virgin but not memory T cells","volume":"258","author":"Fuchs","year":"1992","journal-title":"Science"},{"key":"2023072508040120600_B45"},{"key":"2023072508040120600_B46","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1084\/jem.181.3.993","article-title":"Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance","volume":"181","author":"Rocha","year":"1995","journal-title":"J Exp Med"},{"key":"2023072508040120600_B47","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1016\/0024-3205(94)90087-6","article-title":"The role of anergy in peripheral T cell unresponsiveness","volume":"55","author":"Johnson","year":"1994","journal-title":"Life Sci"},{"key":"2023072508040120600_B48","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/1074-7613(95)90117-5","article-title":"Functionally compromised intermediate in extrathymic CD8+ T cell deletion","volume":"3","author":"Dillon","year":"1995","journal-title":"Immunity"},{"key":"2023072508040120600_B49","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S1074-7613(00)80563-4","article-title":"Modification of CD8+ T cell function during in vivo memory or tolerance induction","volume":"8","author":"Tanchot","year":"1998","journal-title":"Immunity"},{"key":"2023072508040120600_B50","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.4049\/jimmunol.160.10.4719","article-title":"Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance","volume":"160","author":"Pape","year":"1998","journal-title":"J Immunol"},{"key":"2023072508040120600_B51","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1126\/science.280.5361.243","article-title":"Homeostasis and self-tolerance in the immune system: turning lymphocytes off","volume":"280","author":"Parijs","year":"1998","journal-title":"Science"},{"key":"2023072508040120600_B52","doi-asserted-by":"crossref","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":"2023072508040120600_B53","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1128\/jvi.69.2.1059-1070.1995","article-title":"Virus- induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression","volume":"69","author":"Borrow","year":"1995","journal-title":"J Virol"},{"key":"2023072508040120600_B54","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/32588","article-title":"Dendritic cells and the control of immunity","volume":"392","author":"Banchereau","year":"1998","journal-title":"Nature"},{"key":"2023072508040120600_B55","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/30996","article-title":"Help for cytotoxic responses is mediated by CD40 signaling","volume":"393","author":"Bennett","year":"1998","journal-title":"Nature"},{"key":"2023072508040120600_B56","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/30989","article-title":"A conditioned dendritic cell can be a temporal bridge between CD4+ T-helper and a T-killer cell","volume":"393","author":"Ridge","year":"1998","journal-title":"Nature"},{"key":"2023072508040120600_B57","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/31002","article-title":"T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions","volume":"393","author":"Schoenberger","year":"1998","journal-title":"Nature"},{"key":"2023072508040120600_B58","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/300360a0","article-title":"Restricted expression of viral glycoprotein in cells of persistently infected mice","volume":"300","author":"Oldstone","year":"1982","journal-title":"Nature"},{"key":"2023072508040120600_B59","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1084\/jem.187.10.1647-b","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":"2023072508040120600_B60","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/373123a0","article-title":"Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection","volume":"373","author":"Ho","year":"1995","journal-title":"Nature"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/188\/12\/2205\/1688908\/98-1509.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/188\/12\/2205\/1688908\/98-1509.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T09:02:03Z","timestamp":1690275723000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/188\/12\/2205\/7665\/Viral-Immune-Evasion-Due-to-Persistence-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,12,21]]},"references-count":60,"journal-issue":{"issue":"12","published-print":{"date-parts":[[1998,12,21]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.188.12.2205","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,12,21]]}}}