{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:03:10Z","timestamp":1770984190518,"version":"3.50.1"},"reference-count":47,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acute infectious mononucleosis (AIM) induced by Epstein-Barr virus (EBV) infection is characterized by extensive expansion of antigen-specific CD8+ T cells. One potential consequence of this considerable proliferative activity is telomere shortening, which predisposes the EBV-specific cells to replicative senescence. To investigate this, a method was developed that enables the simultaneous identification of EBV specificity of the CD8+ T cells, using major histocompatibility complex (MHC) class I\/peptide complexes, together with telomere length, which is determined by fluorescence in situ hybridization. Despite the considerable expansion, CD8+ EBV-specific T cells in patients with AIM maintain their telomere length relative to CD8+ T cells in normal individuals and relative to CD4+ T cells within the patients themselves and this is associated with the induction of the enzyme telomerase. In 4 patients who were studied up to 12 months after resolution of AIM, telomere lengths of EBV-specific CD8+ T cells were unchanged in 3 but shortened in one individual, who was studied only 5 months after initial onset of infection. Substantial telomere shortening in EBV-specific CD8+ T cells was observed in 3 patients who were studied between 15 months and 14 years after recovery from AIM. Thus, although telomerase activation may preserve the replicative potential of EBV-specific cells in AIM and after initial stages of disease resolution, the capacity of these cells to up-regulate this enzyme after restimulation by the persisting virus may dictate the extent of telomere maintenance in the memory CD8+ T-cell pool over time.<\/jats:p>","DOI":"10.1182\/blood.v97.3.700","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"700-707","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":86,"title":["The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection"],"prefix":"10.1182","volume":"97","author":[{"given":"Fiona J.","family":"Plunkett","sequence":"first","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Vieira D.","family":"Soares","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Annels","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Hislop","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal","family":"Ivory","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Lowdell","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mike","family":"Salmon","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Rickinson","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne N.","family":"Akbar","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology and Department of Haematology, Royal Free and University College Medical School, London; Division of Immunology, Birmingham University Medical School, Birmingham; Division of Immunology, Institute of Food Research, Norwich Research Park, Norwich; and Department of Rheumatology, The Medical School, University of Birmingham, Birmingham, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021220590055000_B1","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":"Ann Rev Immunol."},{"key":"2020021220590055000_B2","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/nm0896-906","article-title":"Large clonal expansions of CD8+ T cells in acute infectious mononucleosis.","volume":"2","author":"Callan","year":"1996","journal-title":"Nat Med."},{"key":"2020021220590055000_B3","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1084\/jem.184.5.1815","article-title":"Development of Epstein-Barr virus-specific memory T cell receptor clonotypes in acute infectious mononucleosis.","volume":"184","author":"Silins","year":"1996","journal-title":"J Exp Med."},{"key":"2020021220590055000_B4","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1084\/jem.178.2.427","article-title":"The significance of low bcl-2 expression by CD45RO+ T cells in normal individuals and patients with acute viral infections: the role of apoptosis in T cell memory.","volume":"178","author":"Akbar","year":"1993","journal-title":"J Exp Med."},{"key":"2020021220590055000_B5","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":"2020021220590055000_B6","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 peptide complexes.","volume":"187","author":"Gallimore","year":"1998","journal-title":"J Exp Med."},{"key":"2020021220590055000_B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3527(08)60057-3","article-title":"Apoptosis in viral-infections.","volume":"45","author":"Razvi","year":"1995","journal-title":"Ad Virus Res."},{"key":"2020021220590055000_B8","doi-asserted-by":"crossref","first-page":"3950","DOI":"10.4049\/jimmunol.164.8.3950","article-title":"Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells.","volume":"164","author":"Grayson","year":"2000","journal-title":"J Immunol."},{"key":"2020021220590055000_B9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0167-5699(97)01003-7","article-title":"Cellular environments and apoptosis: tissue microenvironments control activated T-cell death.","volume":"18","author":"Akbar","year":"1997","journal-title":"Immunol Today."},{"key":"2020021220590055000_B10","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":"2020021220590055000_B11","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":"2020021220590055000_B12","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.4049\/jimmunol.162.8.4521","article-title":"Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence.","volume":"162","author":"Maini","year":"1999","journal-title":"J Immunol."},{"key":"2020021220590055000_B13","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0167-5699(97)01079-7","article-title":"Replicative senescence of T cells: does the Hayflick limit lead to immune exhaustion?","volume":"18","author":"Effros","year":"1997","journal-title":"Immunol Today."},{"key":"2020021220590055000_B14","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/350569a0","article-title":"Structure and function of telomeres.","volume":"350","author":"Blackburn","year":"1991","journal-title":"Nature."},{"key":"2020021220590055000_B15","first-page":"1180","article-title":"Mortality and immortality at the cellular level: a review.","volume":"62","author":"Hayflick","year":"1997","journal-title":"Biochem-Moscow."},{"key":"2020021220590055000_B16","doi-asserted-by":"crossref","first-page":"F17","DOI":"10.1097\/00002030-199607000-00001","article-title":"Shortened telomeres in the expanded CD28\u2212CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.","volume":"10","author":"Effros","year":"1996","journal-title":"AIDS."},{"key":"2020021220590055000_B17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1074-7613(00)80597-X","article-title":"Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential.","volume":"9","author":"Weng","year":"1998","journal-title":"Immunity."},{"key":"2020021220590055000_B18","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/345458a0","article-title":"Telomeres shorten during aging of human fibroblasts.","volume":"345","author":"Harley","year":"1990","journal-title":"Nature."},{"key":"2020021220590055000_B19","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nbt0898-743","article-title":"Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry.","volume":"16","author":"Rufer","year":"1998","journal-title":"Nat Biotech."},{"key":"2020021220590055000_B20","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1084\/jem.190.2.157","article-title":"Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood.","volume":"190","author":"Rufer","year":"1999","journal-title":"J Exp Med."},{"key":"2020021220590055000_B21","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1093\/nar\/26.16.3651","article-title":"Telomere analysis by fluorescence in situ hybridization and flow cytometry.","volume":"26","author":"Hultdin","year":"1998","journal-title":"Nucleic Acids Res."},{"key":"2020021220590055000_B22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/BF00132889","article-title":"Comparison of the telomeric repeat amplification protocol (TRAP) to the new TRAP-eze telomerase detection kit.","volume":"18","author":"Holt","year":"1996","journal-title":"Meth Cell Sci."},{"key":"2020021220590055000_B23","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1046\/j.1365-2567.1998.00556.x","article-title":"Comparison of two techniques for the molecular tracking of specific T-cell responses; CD4+ human T-cell clones persist in a stable hierarchy but at a lower frequency than clones in the CD8 population.","volume":"94","author":"Maini","year":"1998","journal-title":"Immunology."},{"key":"2020021220590055000_B24","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S0167-5699(99)01472-3","article-title":"T-cell clonality in immune responses.","volume":"20","author":"Maini","year":"1999","journal-title":"Immunol Today."},{"key":"2020021220590055000_B25","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1084\/jem.180.5.1943","article-title":"The specific recognition by macrophages of CD8+CD45RO+ T cells undergoing apoptosis\u2014a mechanism for T cell clearance during resolution of viral-infections.","volume":"180","author":"Akbar","year":"1994","journal-title":"J Exp Med."},{"key":"2020021220590055000_B26","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1084\/jem.190.2.153","article-title":"Telomere length, aging, and somatic cell turnover.","volume":"190","author":"Hodes","year":"1999","journal-title":"J Exp Med."},{"key":"2020021220590055000_B27","doi-asserted-by":"crossref","first-page":"5702","DOI":"10.4049\/jimmunol.160.12.5702","article-title":"Cutting edge: antigen-dependent regulation of telomerase activity in murine T cells.","volume":"160","author":"Hathcock","year":"1998","journal-title":"J Immunol."},{"key":"2020021220590055000_B28","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.4049\/jimmunol.165.9.4831","article-title":"Changing patterns of dominant T cell receptor usage with maturation of an Epstein-Barr virus-specific cytotoxic T cell response.","volume":"9","author":"Annels","year":"2000","journal-title":"J Immunol."},{"key":"2020021220590055000_B29","first-page":"508","article-title":"Factors that influence activated CD8+ T-cell apoptosis in patients with acute herpesvirus infections: loss of costimulatory molecules CD28, CD5 and CD6 but relative maintenance of Bax and Bcl-X expression.","volume":"88","author":"Borthwick","year":"1996","journal-title":"Immunology."},{"key":"2020021220590055000_B30","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1093\/intimm\/12.7.1005","article-title":"Loss of CD28 expression on CD8+ T cells is induced by IL-2R\u03b3-chain signalling cytokines and type I interferon and increases susceptibility to activation induced apoptosis.","volume":"12","author":"Borthwick","year":"2000","journal-title":"Int Immunol."},{"key":"2020021220590055000_B31","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/0531-5565(94)90073-6","article-title":"Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence.","volume":"29","author":"Effros","year":"1994","journal-title":"Exp Gerontol."},{"key":"2020021220590055000_B32","doi-asserted-by":"crossref","first-page":"3587","DOI":"10.4049\/jimmunol.156.10.3587","article-title":"Shortened telomeres in clonally expanded CD28\u2212CD8\u2212+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts.","volume":"156","author":"Monteiro","year":"1996","journal-title":"J Immunol."},{"key":"2020021220590055000_B33","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1126\/science.288.5466.675","article-title":"Control of homeostasis of CD8+ memory T cells by opposing cytokines.","volume":"288","author":"Ku","year":"2000","journal-title":"Science."},{"key":"2020021220590055000_B34","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.189.3.521","article-title":"Type I interferons keep activated T cells alive.","volume":"189","author":"Marrack","year":"1999","journal-title":"J Exp Med."},{"key":"2020021220590055000_B35","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1073\/pnas.95.7.3810","article-title":"Cytokine-induced survival of activated T cells in vitro and in vivo.","volume":"95","author":"Vella","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021220590055000_B36","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/(SICI)1521-4141(199903)29:03<1041::AID-IMMU1041>3.0.CO;2-#","article-title":"Interferon \u03b2 mediates stromal cell rescue of T cells from apoptosis.","volume":"29","author":"Pilling","year":"1999","journal-title":"Eur J Immunol."},{"key":"2020021220590055000_B37","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1002\/(SICI)1521-4141(199908)29:08<2603::AID-IMMU2603>3.0.CO;2-L","article-title":"Inhibition of T cell apoptosis by IFN-\u03b2 rapidly reverses nuclear translocation of protein kinase C-\u03b4.","volume":"29","author":"Scheel-Toellner","year":"1999","journal-title":"Eur J Immunol."},{"key":"2020021220590055000_B38","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/eji.1830260204","article-title":"Interleukin-2 receptor common \u03b3-chain signalling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl- xS) gene expression.","volume":"26","author":"Akbar","year":"1996","journal-title":"Eur J Immunol."},{"key":"2020021220590055000_B39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S1074-7613(00)80091-6","article-title":"Following the development of a CD4 T cell response in vivo: from activation to memory formation.","volume":"11","author":"Garcia","year":"1999","journal-title":"Immunity."},{"key":"2020021220590055000_B40","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1172\/JCI119178","article-title":"Inhibition of T cell apoptosis in the rheumatoid synovium.","volume":"99","author":"Salmon","year":"1997","journal-title":"J Clin Invest."},{"key":"2020021220590055000_B41","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/347400a0","article-title":"Hypervariable ultra-long telomeres in mice.","volume":"347","author":"Kipling","year":"1990","journal-title":"Nature."},{"key":"2020021220590055000_B42","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.4049\/jimmunol.152.8.3740","article-title":"Aged T-cells are hyporesponsive to costimulation mediated by CD28.","volume":"152","author":"Engwerda","year":"1994","journal-title":"J Immunol."},{"key":"2020021220590055000_B43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1600-065X.1999.tb01327.x","article-title":"Stimulation of naive and memory T cells by cytokines.","volume":"170","author":"Tough","year":"1999","journal-title":"Immunol Rev."},{"key":"2020021220590055000_B44","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0140-6736(97)08256-1","article-title":"Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants.","volume":"351","author":"Wynn","year":"1998","journal-title":"Lancet."},{"key":"2020021220590055000_B45","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/0167-5699(93)90181-J","article-title":"A possible role for Bcl-2 in regulating T cell memory\u2014a balancing act between cell-death and survival.","volume":"14","author":"Akbar","year":"1993","journal-title":"Immunol Today."},{"key":"2020021220590055000_B46","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0167-5699(00)01652-2","article-title":"IFN-\u03b1 and IFN-\u03b2: a link between immune memory and chronic inflammation.","volume":"21","author":"Akbar","year":"2000","journal-title":"Immunol Today."},{"key":"2020021220590055000_B47","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.1997.tb01022.x","article-title":"Aging and the immune system.","volume":"160","author":"Hodes","year":"1997","journal-title":"Immunol Rev."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/97\/3\/700\/1670726\/700.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/97\/3\/700\/1670726\/700.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T20:10:24Z","timestamp":1682280624000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/97\/3\/700\/52767\/The-flow-cytometric-analysis-of-telomere-length-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,2,1]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2001,2,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v97.3.700","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2001,2,1]]}}}