{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:32:49Z","timestamp":1792672369249,"version":"4.5.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2009,6,1]],"date-time":"2009-06-01T00:00:00Z","timestamp":1243814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The failure of CD8+ T cells to respond to chronic infection has been termed \u201cexhaustion\u201d and describes the condition in which CD8+ T cells exhibit reduced differentiation, proliferation, and effector function. CD8+ T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8+ T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8+ T cell impairment, that Ag-driven loss of virus-specific CD8+ T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8+ T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8+ T cells in chronic infection.<\/jats:p>","DOI":"10.4049\/jimmunol.0800997","type":"journal-article","created":{"date-parts":[[2009,5,19]],"date-time":"2009-05-19T17:00:29Z","timestamp":1242752429000},"page":"6697-6708","source":"Crossref","is-referenced-by-count":175,"title":["Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8+ T Cell Exhaustion"],"prefix":"10.1093","volume":"182","author":[{"given":"Christine M","family":"Bucks","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian A","family":"Norton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina C","family":"Boesteanu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne M","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D","family":"Katsikis","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA 19129"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,6,1]]},"reference":[{"key":"2025032715455863800_R1","first-page":"4650","article-title":"Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.","volume-title":"J. Virol.","year":"1994"},{"key":"2025032715455863800_R2","first-page":"13","article-title":"Cytotoxic T-cell immunity to influenza.","volume-title":"N. Engl. J. Med.","year":"1983"},{"key":"2025032715455863800_R3","first-page":"857","article-title":"Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.","volume-title":"Science","year":"1999"},{"key":"2025032715455863800_R4","first-page":"63","article-title":"HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function.","volume-title":"J. Exp. Med.","year":"2000"},{"key":"2025032715455863800_R5","first-page":"10249","article-title":"A significant number of human immunodeficiency virus epitope-specific cytotoxic T lymphocytes detected by tetramer binding do not produce \u03b3 interferon.","volume-title":"J. Virol.","year":"2000"},{"key":"2025032715455863800_R6","first-page":"2505","article-title":"Persistent numbers of tetramer+ CD8+ T cells, but loss of interferon-\u03b3+ HIV-specific T cells during progression to AIDS.","volume-title":"Blood","year":"2002"},{"key":"2025032715455863800_R7","first-page":"153","article-title":"HIV-specific CD8+ T cells: serial killers condemned to die?.","volume-title":"Curr. HIV Res.","year":"2004"},{"key":"2025032715455863800_R8","first-page":"4215","article-title":"Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.","volume-title":"J. Virol.","year":"2007"},{"key":"2025032715455863800_R9","first-page":"5707","article-title":"Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.","volume-title":"J. Virol.","year":"2004"},{"key":"2025032715455863800_R10","first-page":"5550","article-title":"Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus.","volume-title":"J. Virol.","year":"2001"},{"key":"2025032715455863800_R11","first-page":"3447","article-title":"Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection.","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032715455863800_R12","first-page":"106","article-title":"Skewed maturation of memory HIV-specific CD8 T lymphocytes.","volume-title":"Nature","year":"2001"},{"key":"2025032715455863800_R13","first-page":"677","article-title":"High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function.","volume-title":"Eur. J. Immunol.","year":"2001"},{"key":"2025032715455863800_R14","first-page":"859","article-title":"Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy.","volume-title":"Cell Death Differ.","year":"2005"},{"key":"2025032715455863800_R15","first-page":"871","article-title":"Increased CD95\/Fas-induced apoptosis of HIV-specific CD8+ T cells.","volume-title":"Immunity","year":"2001"},{"key":"2025032715455863800_R16","first-page":"4204","article-title":"Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections.","volume-title":"J. Immunol.","year":"2004"},{"key":"2025032715455863800_R17","first-page":"477","article-title":"Ablation of CD8 and CD4 T cell responses by high viral loads.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032715455863800_R18","first-page":"1383","article-title":"Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes.","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2025032715455863800_R19","first-page":"4911","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.","volume-title":"J. Virol.","year":"2003"},{"key":"2025032715455863800_R20","first-page":"3578","article-title":"Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection.","volume-title":"J. Virol.","year":"2004"},{"key":"2025032715455863800_R21","first-page":"3379","article-title":"Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the central nervous system.","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032715455863800_R22","first-page":"595","article-title":"Antiviral CD8+ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2025032715455863800_R23","first-page":"2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function.","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2025032715455863800_R24","first-page":"829","article-title":"Critical role for perforin-, Fas\/FasL-, and TNFR1-mediated cytotoxic pathways in down-regulation of antigen-specific T cells during persistent viral infection.","volume-title":"J. Virol.","year":"2002"},{"key":"2025032715455863800_R25","first-page":"1719","article-title":"Organ-specific selection of viral variants during chronic infection.","volume-title":"J. Exp. Med.","year":"1988"},{"key":"2025032715455863800_R26","first-page":"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-title":"J. Exp. Med.","year":"1984"},{"key":"2025032715455863800_R27","first-page":"6983","article-title":"The role of antigen in the localization of naive, acutely activated, and memory CD8+ T cells to the lung during influenza pneumonia.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032715455863800_R28","first-page":"536","article-title":"In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses.","volume-title":"Nat. Immunol.","year":"2002"},{"key":"2025032715455863800_R29","first-page":"1947","article-title":"Induction of bystander T cell proliferation by viruses and type I interferon in vivo.","volume-title":"Science","year":"1996"},{"key":"2025032715455863800_R30","first-page":"6406","article-title":"Newly activated T cells promote maturation of bystander dendritic cells but not IL-12 production.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032715455863800_R31","first-page":"809","article-title":"CD8+ T cell contraction is controlled by early inflammation.","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2025032715455863800_R32","first-page":"7011","article-title":"Multiple anti-interferon actions of the influenza A virus NS1 protein.","volume-title":"J. Virol.","year":"2007"},{"key":"2025032715455863800_R33","first-page":"827","article-title":"Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection.","volume-title":"Immunity","year":"2007"},{"key":"2025032715455863800_R34","first-page":"2263","article-title":"Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection.","volume-title":"J. Exp. Med.","year":"2006"},{"key":"2025032715455863800_R35","first-page":"217","article-title":"The role of programming in memory T-cell development.","volume-title":"Curr. Opin. Immunol.","year":"2004"},{"key":"2025032715455863800_R36","first-page":"93","article-title":"Changing immunodominance patterns in antiviral CD8 T-cell responses after loss of epitope presentation or chronic antigenic stimulation.","volume-title":"Virology","year":"2003"},{"key":"2025032715455863800_R37","first-page":"1675","article-title":"Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection.","volume-title":"J. Clin. Invest.","year":"2006"},{"key":"2025032715455863800_R38","first-page":"169","article-title":"Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2025032715455863800_R39","first-page":"112","article-title":"Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.","volume-title":"Science","year":"1997"},{"key":"2025032715455863800_R40","first-page":"3382","article-title":"Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes.","volume-title":"Proc. Natl. Acad. Sci. 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Med.","year":"2006"},{"key":"2025032715455863800_R46","first-page":"2545","article-title":"Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression.","volume-title":"J. Virol.","year":"2007"},{"key":"2025032715455863800_R47","first-page":"86","article-title":"Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.","volume-title":"Nature","year":"1998"},{"key":"2025032715455863800_R48","first-page":"1663","article-title":"Inactivated influenza virus, when presented on dendritic cells, elicits human CD8+ cytolytic T cell responses.","volume-title":"J. Exp. Med.","year":"1995"},{"key":"2025032715455863800_R49","first-page":"10861","article-title":"Early establishment and antigen dependence of simian immunodeficiency virus-specific CD8+ T-cell defects.","volume-title":"J. Virol.","year":"2007"},{"key":"2025032715455863800_R50","first-page":"941","article-title":"Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection.","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2025032715455863800_R51","first-page":"16004","article-title":"Antigen-independent memory CD8 T cells do not develop during chronic viral infection.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2025032715455863800_R52","first-page":"928","article-title":"SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection.","volume-title":"Blood","year":"2007"},{"key":"2025032715455863800_R53","first-page":"5819","article-title":"Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination.","volume-title":"J. Virol.","year":"2007"},{"key":"2025032715455863800_R54","first-page":"116","article-title":"Programmed death (PD)-1:PD-ligand 1\/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis.","volume-title":"J. Immunol.","year":"2008"},{"key":"2025032715455863800_R55","first-page":"88","article-title":"CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.","volume-title":"Nature","year":"2005"},{"key":"2025032715455863800_R56","first-page":"9762","article-title":"Diminished primary and secondary influenza virus-specific CD8+ T-cell responses in CD4-depleted Ig\u2212\/\u2212 mice.","volume-title":"J. Virol.","year":"2000"},{"key":"2025032715455863800_R57","first-page":"337","article-title":"Requirement for CD4 T cell help in generating functional CD8 T cell memory.","volume-title":"Science","year":"2003"},{"key":"2025032715455863800_R58","first-page":"339","article-title":"Defective CD8 T cell memory following acute infection without CD4 T cell help.","volume-title":"Science","year":"2003"},{"key":"2025032715455863800_R59","first-page":"1072","article-title":"CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge.","volume-title":"J. 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