{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:21:52Z","timestamp":1778498512675,"version":"3.51.4"},"reference-count":41,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During acute infection, latent and lytic Epstein-Barr virus (EBV) epitope-specific CD8+ T cells have a CD45RO+CD45RA\u2212 phenotype. However, after resolution of the infection, a large proportion of these cells, particularly those specific for lytic viral epitopes, re-express the CD45RA molecule. The role of CD8+ CD45RA+ T cells in ongoing immunity to EBV and other viruses is unknown. We now demonstrate that, relative to their CD45RO+ counterparts, the EBV-specific CD8+ T cells that revert to CD45RA expression after acute infectious mononucleosis are not in cell cycle, have longer telomeres, and are more resistant to apoptosis partly because of increased Bcl-2 expression. However, the EBV-specific CD8+CD45RA+ T cells have shorter telomeres than the total CD8+ CD45RA+ T-cell pool and predominantly express low levels of the CCR7 chemokine receptor, indicating that they are not naive cells. In addition, EBV-specific CD8+CD45RA+ T cells can be induced to proliferate and exhibit potent cytotoxic activity against target cells loaded with specific peptide. Our results strongly suggest, therefore, that EBV-specific CD8+ CD45RA+ T cells represent a stabilized virus-specific memory pool and not terminally differentiated effector cells. The identification of mechanisms that enable stable virus-specific CD8+ T cells to persist after acute infection may lead to the enhancement of antiviral immunity in immunocompromised and elderly persons.<\/jats:p>","DOI":"10.1182\/blood-2002-01-0160","type":"journal-article","created":{"date-parts":[[2002,10,11]],"date-time":"2002-10-11T18:33:52Z","timestamp":1034361232000},"page":"933-940","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":114,"title":["Epstein-Barr virus\u2013specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential"],"prefix":"10.1182","volume":"100","author":[{"given":"Padraic J.","family":"Dunne","sequence":"first","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Jeffery M.","family":"Faint","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Nancy H.","family":"Gudgeon","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Jean M.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Fiona J.","family":"Plunkett","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Maria Vieira D.","family":"Soares","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Andrew D.","family":"Hislop","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Nicola E.","family":"Annels","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Alan B.","family":"Rickinson","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Mike","family":"Salmon","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]},{"given":"Arne N.","family":"Akbar","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Immunology, Royal Free and University College Medical School, London; the Cancer Research Campaign Institute for Cancer Studies, Birmingham University Medical School; and the Medical Research Council Centre for Immune Regulation, Birmingham University Medical School, United Kingdom."}]}],"member":"234","reference":[{"key":"2020021223062903300_B1","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":"2020021223062903300_B2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev.immunol.15.1.405","article-title":"Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection.","volume":"15","author":"Rickinson","year":"1997","journal-title":"Ann Rev Immunol."},{"key":"2020021223062903300_B3","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: a mechanism for T cell clearance during resolution of viral infections.","volume":"180","author":"Akbar","year":"1994","journal-title":"J Exp Med."},{"key":"2020021223062903300_B4","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1182\/blood.V80.2.452.452","article-title":"Apoptotic cell-death of primed CD45RO+ lymphocytes-T in Epstein-Barr virus-induced infectious mononucleosis.","volume":"80","author":"Uehara","year":"1992","journal-title":"Blood."},{"key":"2020021223062903300_B5","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.4049\/jimmunol.165.9.4831","article-title":"Changing patterns of dominant TCR usage with maturation of an EBV-specific cytotoxic T cell response.","volume":"165","author":"Annels","year":"2000","journal-title":"J Immunol."},{"key":"2020021223062903300_B6","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1172\/JCI10590","article-title":"CD8+ T-cell selection, function, and death in the primary immune response in vivo.","volume":"106","author":"Callan","year":"2000","journal-title":"J Clin Invest."},{"key":"2020021223062903300_B7","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1172\/JCI4225","article-title":"A functional link for major TCR expansions in healthy adults caused by persistent Epstein-Barr virus infection.","volume":"102","author":"Silins","year":"1998","journal-title":"J Clin Invest."},{"key":"2020021223062903300_B8","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":"2020021223062903300_B9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1600-065X.1997.tb01026.x","article-title":"Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.","volume":"160","author":"Weng","year":"1997","journal-title":"Immunol Rev."},{"key":"2020021223062903300_B10","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0167-5699(00)01714-X","article-title":"Aging of lymphocytes and lymphocytes in the aged.","volume":"21","author":"Globerson","year":"2000","journal-title":"Immunol Today."},{"key":"2020021223062903300_B11","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":"2020021223062903300_B12","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1182\/blood.V97.3.700","article-title":"The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection.","volume":"97","author":"Plunkett","year":"2001","journal-title":"Blood."},{"key":"2020021223062903300_B13","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-2 receptor g-chain signaling cytokines and type II IFN, and increases susceptibility to activation-induced apoptosis.","volume":"12","author":"Borthwick","year":"2000","journal-title":"Int Immunol."},{"key":"2020021223062903300_B14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.4049\/jimmunol.167.1.212","article-title":"Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics.","volume":"167","author":"Faint","year":"2001","journal-title":"J Immunol."},{"key":"2020021223062903300_B15","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.4049\/jimmunol.167.4.2019","article-title":"EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function.","volume":"167","author":"Hislop","year":"2001","journal-title":"J Immunol."},{"key":"2020021223062903300_B16","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":"2020021223062903300_B17","doi-asserted-by":"crossref","first-page":"7080","DOI":"10.4049\/jimmunol.162.12.7080","article-title":"Human virus-specific CD8+ CTL clones revert from CD45ROhigh to CD45RAhigh in vivo: CD45RAhigh CD8+ T cells comprise both naive and memory cells.","volume":"162","author":"Wills","year":"1999","journal-title":"J Immunol."},{"key":"2020021223062903300_B18","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/35065118","article-title":"Skewed maturation of memory HIV-specific CD8 T lymphocytes.","volume":"410","author":"Champagne","year":"2001","journal-title":"Nature."},{"key":"2020021223062903300_B19","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1084\/jem.190.5.705","article-title":"High frequencies of naive Melan-A\/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals.","volume":"190","author":"Pittet","year":"1999","journal-title":"J Exp Med."},{"key":"2020021223062903300_B20","doi-asserted-by":"crossref","first-page":"8140","DOI":"10.1128\/JVI.74.17.8140-8150.2000","article-title":"Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors.","volume":"74","author":"Gillespie","year":"2000","journal-title":"J Virol."},{"key":"2020021223062903300_B21","doi-asserted-by":"crossref","first-page":"5729","DOI":"10.4049\/jimmunol.165.10.5729","article-title":"Clonal expansions in acute EBV infection are detectable in the CD8 and not the CD4 subset and persist with a variable CD45 phenotype.","volume":"165","author":"Maini","year":"2000","journal-title":"J Immunol."},{"key":"2020021223062903300_B22","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1084\/jem.179.2.609","article-title":"Clonal populations of T cells in normal elderly humans: the T cell equivalent to benign monoclonal gammopathy.","volume":"179","author":"Posnett","year":"1994","journal-title":"J Exp Med."},{"key":"2020021223062903300_B23","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/44385","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature."},{"key":"2020021223062903300_B24","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/1521-4141(200103)31:3<677::AID-IMMU677>3.0.CO;2-M","article-title":"High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function.","volume":"31","author":"Kostense","year":"2001","journal-title":"Eur J Immunol."},{"key":"2020021223062903300_B25","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.4049\/jimmunol.133.4.1710","article-title":"Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.","volume":"133","author":"Gerdes","year":"1984","journal-title":"J Immunol."},{"key":"2020021223062903300_B26","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":"2020021223062903300_B27","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":"2020021223062903300_B28","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":"2020021223062903300_B29","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.4049\/jimmunol.160.7.3236","article-title":"CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C\u2212) to TCR\/CD8 signaling in response to antigen.","volume":"160","author":"Curtsinger","year":"1998","journal-title":"J Immunol."},{"key":"2020021223062903300_B30","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":"2020021223062903300_B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/smim.1996.0050","article-title":"The molecular regulation of lymphocyte apoptosis.","volume":"9","author":"Lenardo","year":"1997","journal-title":"Semin Immunol."},{"key":"2020021223062903300_B32","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":"2020021223062903300_B33","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/0092-8674(91)90361-2","article-title":"BCL-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes.","volume":"67","author":"Sentman","year":"1991","journal-title":"Cell."},{"key":"2020021223062903300_B34","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/0092-8674(91)90362-3","article-title":"BCL-2 transgene inhibits T cell death and perturbs thymic self-censorship.","volume":"67","author":"Strasser","year":"1991","journal-title":"Cell."},{"key":"2020021223062903300_B35","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/eji.1830190403","article-title":"Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200).","volume":"19","author":"Pilarski","year":"1989","journal-title":"Eur J Immunol."},{"key":"2020021223062903300_B36","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1600-065X.1991.tb00600.x","article-title":"Clonal deletion of autospecific lymphocytes-B.","volume":"122","author":"Nemazee","year":"1991","journal-title":"Immunol Rev."},{"key":"2020021223062903300_B37","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1002\/eji.1830210819","article-title":"Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis.","volume":"21","author":"Liu","year":"1991","journal-title":"Eur J Immunol."},{"key":"2020021223062903300_B38","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1084\/jem.183.4.1377","article-title":"Concurrent engagement of CD40 and the antigen receptor protects naive and memory human B cells from APO-1\/Fas-mediated apoptosis.","volume":"183","author":"Lagresle","year":"1996","journal-title":"J Exp Med."},{"key":"2020021223062903300_B39","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.4049\/jimmunol.152.6.2821","article-title":"Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40.","volume":"152","author":"Parry","year":"1994","journal-title":"J Immunol."},{"key":"2020021223062903300_B40","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.1002\/(SICI)1521-4141(199909)29:09<2908::AID-IMMU2908>3.0.CO;2-8","article-title":"Distribution of human CMV-specific memory T cells among the CD8(pos.) subsets defined by CD57, CD27, and CD45 isoforms.","volume":"29","author":"Kern","year":"1999","journal-title":"Eur J Immunol."},{"key":"2020021223062903300_B41","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1084\/jem.186.9.1407","article-title":"Phenotypic and functional separation of memory and effector human CD8(+) T cells.","volume":"186","author":"Hamann","year":"1997","journal-title":"J Exp Med."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/100\/3\/933\/1684917\/h81502000933.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/100\/3\/933\/1684917\/h81502000933.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T08:21:44Z","timestamp":1682324504000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/100\/3\/933\/16443\/EpsteinBarr-virusspecific-CD8-T-cells-that"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,8,1]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2002,8,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2002-01-0160","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2002,8,1]]}}}