{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:41:34Z","timestamp":1789634494699,"version":"build-2803163510"},"reference-count":34,"publisher":"Rockefeller University Press","issue":"7","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,4,7]]},"abstract":"<jats:p>Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I\u2013restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized \u201cnaive\u201d TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not \u03b1\/\u03b2-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.<\/jats:p>","DOI":"10.1084\/jem.185.7.1241","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"1241-1252","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":126,"title":["Bystander Activation of Cytotoxic T Cells: Studies on the Mechanism and Evaluation of In Vivo Significance in a Transgenic Mouse Model"],"prefix":"10.1084","volume":"185","author":[{"given":"Stephan","family":"Ehl","sequence":"first","affiliation":[{"name":"From the Institute of Experimental Immunology, Department of Pathology, University of Z\u00fcrich, CH-8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Hombach","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, Department of Pathology, University of Z\u00fcrich, CH-8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aichele","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, Department of Pathology, University of Z\u00fcrich, CH-8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Hengartner","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, Department of Pathology, University of Z\u00fcrich, CH-8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf M.","family":"Zinkernagel","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, Department of Pathology, University of Z\u00fcrich, CH-8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1997,4,7]]},"reference":[{"key":"2023072915262629500_B1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0167-5699(90)90083-L","article-title":"Is T cell memory maintained by cross-reactive stimulation?","volume":"11","author":"Beverly","year":"1990","journal-title":"Immunol Today"},{"key":"2023072915262629500_B2","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1084\/jem.179.6.1933","article-title":"Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses","volume":"179","author":"Selin","year":"1994","journal-title":"J Exp Med"},{"key":"2023072915262629500_B3","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1084\/jem.183.6.2489","article-title":"Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infection","volume":"183","author":"Selin","year":"1996","journal-title":"J Exp Med"},{"key":"2023072915262629500_B4","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1084\/jem.180.3.1159","article-title":"Antigen-independent activation of naive and memory resting cells by a cytokine combination","volume":"180","author":"Unutmaz","year":"1994","journal-title":"J Exp Med"},{"key":"2023072915262629500_B5","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1126\/science.272.5270.1947","article-title":"Induction of bystander T cell proliferation by viruses and type I interferon in vivo","volume":"272","author":"Tough","year":"1996","journal-title":"Science (Wash DC)"},{"key":"2023072915262629500_B6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1084\/jem.177.2.317","article-title":"High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response","volume":"177","author":"Nahill","year":"1993","journal-title":"J Exp Med"},{"key":"2023072915262629500_B7","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.4049\/jimmunol.136.4.1186","article-title":"Induction of alloreactive cytotoxic T cells by acute virus infection of mice","volume":"136","author":"Yang","year":"1986","journal-title":"J Immunol"},{"key":"2023072915262629500_B8","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.4049\/jimmunol.142.5.1710","article-title":"Virusinduced polyclonal cytotoxic T lymphocyte stimulation","volume":"142","author":"Yang","year":"1989","journal-title":"J Immunol"},{"key":"2023072915262629500_B9","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.4049\/jimmunol.149.7.2406","article-title":"Cytotoxic T lymphocytes show HLA-C\u2013restricted recognition of EBV-bearing cells and allorecognition of HLA class I molecules presenting selfpeptides","volume":"149","author":"Schendel","year":"1992","journal-title":"J Immunol"},{"key":"2023072915262629500_B10","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/eji.1830170717","article-title":"Multiple HLA class I\u2013dependent cytotoxicities constitute the \u201cnon-HLA-restricted\u201d response to infectious mononucleosis","volume":"17","author":"Strang","year":"1987","journal-title":"Eur J Immunol"},{"key":"2023072915262629500_B11","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1084\/jem.158.6.1804","article-title":"Cross-reactivity of self-HLA-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes for allo-HLA determinants","volume":"158","author":"Gaston","year":"1983","journal-title":"J Exp Med"},{"key":"2023072915262629500_B12","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/0092-8674(87)90507-1","article-title":"Molecular mimicry and autoimmune disease","volume":"50","author":"Oldstone","year":"1987","journal-title":"Cell"},{"key":"2023072915262629500_B13","doi-asserted-by":"crossref","first-page":"9102","DOI":"10.1073\/pnas.93.17.9102","article-title":"Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function","volume":"93","author":"Zal","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072915262629500_B14","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/0092-8674(92)90453-J","article-title":"Exclusion and inclusion of \u03b1 and \u03b2 T cell receptor alleles","volume":"69","author":"Borgulya","year":"1992","journal-title":"Cell"},{"key":"2023072915262629500_B15","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1084\/jem.174.6.1371","article-title":"T cell receptor genes in a series of class I major histocompatibility complex\u2013restricted cytotoxic T lymphocyte clones specific for a plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire","volume":"174","author":"Casanova","year":"1991","journal-title":"J Exp Med"},{"key":"2023072915262629500_B16","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1084\/jem.178.5.1807","article-title":"Expression of two \u03b1 chains on the surface of T cells in T cell receptor transgenic mice","volume":"178","author":"Heath","year":"1993","journal-title":"J Exp Med"},{"key":"2023072915262629500_B17","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1002\/eji.1830250622","article-title":"Expression of two T cell receptor \u03b1 chains on the surface of normal murine T cells","volume":"25","author":"Heath","year":"1995","journal-title":"Eur J Immunol"},{"key":"2023072915262629500_B18","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1126\/science.8211163","article-title":"Expression of two T cell receptor \u03b1 chains: dual receptor T cells","volume":"262","author":"Padovan","year":"1993","journal-title":"Science (Wash DC)"},{"key":"2023072915262629500_B19","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature (Lond)"},{"key":"2023072915262629500_B20","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2\u2013deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangements","volume":"68","author":"Shinkai","year":"1992","journal-title":"Cell"},{"key":"2023072915262629500_B21","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1126\/science.8009221","article-title":"Functional role of type I and type II interferons in antiviral defense","volume":"264","author":"M\u00fcller","year":"1994","journal-title":"Science (Wash DC)"},{"key":"2023072915262629500_B22","doi-asserted-by":"crossref","first-page":"5185","DOI":"10.4049\/jimmunol.150.11.5185","article-title":"Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and tumor necrosis factor-\u03b1","volume":"150","author":"Ohashi","year":"1993","journal-title":"J Immunol"},{"key":"2023072915262629500_B23","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1084\/jem.164.4.1075","article-title":"T cell\u2013mediated hepatitis in mice infected with lymphocytic choriomeningitis virus","volume":"164","author":"Zinkernagel","year":"1986","journal-title":"J Exp Med"},{"key":"2023072915262629500_B24","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0166-0934(91)90018-U","article-title":"Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates","volume":"33","author":"Battegay","year":"1991","journal-title":"J Virol Methods"},{"key":"2023072915262629500_B25","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":"2023072915262629500_B26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0167-5699(91)90050-4","article-title":"The synergy between naive and memory T cells during activation","volume":"12","author":"Akbar","year":"1991","journal-title":"Immunol Today"},{"key":"2023072915262629500_B27","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/eji.1830170707","article-title":"The immune response of the mouse to lymphocytic choriomeningitis virus. V. High numbers of cytolytic T lymphocytes are generated in the spleen during acute infection","volume":"17","author":"Moskophidis","year":"1987","journal-title":"Eur J Immunol"},{"key":"2023072915262629500_B28","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0092-8674(91)90164-T","article-title":"Ablation of \u201ctolerance\u201d and induction of diabetes by virus infection in viral antigen transgenic mice","volume":"65","author":"Ohashi","year":"1991","journal-title":"Cell"},{"key":"2023072915262629500_B29","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.4049\/jimmunol.157.12.5300","article-title":"Memory T cell development in the absence of specific antigen priming","volume":"157","author":"Lee","year":"1996","journal-title":"J Immunol"},{"key":"2023072915262629500_B30","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/0952-7915(94)90140-6","article-title":"Specificity and editing by apoptosis of virus-induced cytotoxic T lymphocytes","volume":"6","author":"Selin","year":"1994","journal-title":"Curr Opin Immunol"},{"key":"2023072915262629500_B31","first-page":"35","article-title":"MHC molecules as peptide receptors","volume":"5","author":"Rammensee","year":"1993","journal-title":"Curr Biol"},{"key":"2023072915262629500_B32","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1073\/pnas.91.2.767","article-title":"Minimal structural requirements for peptide presentation by major histocompatibility class II molecules: implications in induction of autoimmunity","volume":"91","author":"Gautam","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072915262629500_B33","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1600-065X.1996.tb00909.x","article-title":"Immunopathology or organ-specific autoimmunity as a consequence of virus infection","volume":"152","author":"Aichele","year":"1996","journal-title":"Immunol Rev"},{"key":"2023072915262629500_B34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/359079a0","article-title":"Infection breaks T-cell tolerance","volume":"359","author":"R\u00f6cken","year":"1992","journal-title":"Nature (Lond)"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/185\/7\/1241\/1897346\/5478.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/185\/7\/1241\/1897346\/5478.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T15:26:55Z","timestamp":1690644415000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/185\/7\/1241\/25599\/Bystander-Activation-of-Cytotoxic-T-Cells-Studies"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,4,7]]},"references-count":34,"journal-issue":{"issue":"7","published-print":{"date-parts":[[1997,4,7]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.185.7.1241","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,4,7]]}}}