{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:23:46Z","timestamp":1778624626752,"version":"3.51.4"},"reference-count":55,"publisher":"The Royal Society","issue":"1395","license":[{"start":{"date-parts":[[2000,3,29]],"date-time":"2000-03-29T00:00:00Z","timestamp":954288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Phil. Trans. R. Soc. Lond. B"],"published-print":{"date-parts":[[2000,3,29]]},"abstract":"<jats:p>\n                    The functional units of immune response are lymphocyte clones. Analysis of lymphocyte life span\n                    <jats:italic>in vivo<\/jats:italic>\n                    shows that the overall turnover of CD4 and CD8 lymphocytes does not differ greatly. Recently, molecular methods have been developed which allow a global analysis of T\u2013cell clones responding to an antigen\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We have used a sensitive, modified heteroduplex analysis to follow T\u2013cell clones responding to Epstein\u2013Barr virus in acute infectious mononucleosis (AIM). Strikingly, all the many large clones detected in freshly isolated AIM blood were found within the CD8 fraction. CD4 clonal populations responding to the soluble recall antigen tetanus toxoid could only be detected after\n                    <jats:italic>in vitro<\/jats:italic>\n                    re\u2013stimulation. These data imply that CD4 responses may be more polyclonal than those of CD8 cells and that the size of CD4 clones is more tightly regulated. Several molecular mechanisms may contribute to this. Up\u2013regulation of telomerase allows very large expansions of CD8 cells to occur without exhaustion of proliferative capacity.\n                  <\/jats:p>","DOI":"10.1098\/rstb.2000.0580","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T19:55:21Z","timestamp":1027713321000},"page":"401-406","source":"Crossref","is-referenced-by-count":19,"title":["Differences in the regulation of CD4 and CD8 T\u2013cell clones during immune responses"],"prefix":"10.1098","volume":"355","author":[{"given":"Peter C. L.","family":"Beverley","sequence":"first","affiliation":[{"name":"Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7.N.N, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mala K.","family":"Maini","sequence":"additional","affiliation":[{"name":"The Institute of HePatology, University College London Medical School, London WC1E 6HX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2000,3,29]]},"reference":[{"key":"p_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.2.427"},{"key":"p_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5284.94"},{"key":"p_3","doi-asserted-by":"crossref","unstructured":"Bell E. B. & Sparshott S. M. 1990 Interconversion of CD45 subsets of CD4 Tcells in vivo. Nature 348 163^166.","DOI":"10.1038\/348163a0"},{"key":"p_4","doi-asserted-by":"crossref","unstructured":"Beverley P. C. L. 1996 Generation of T cell memory. Curr. Opin. Immunol. 8 327^330.","DOI":"10.1016\/S0952-7915(96)80120-8"},{"key":"p_5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.4049\/jimmunol.162.1.9","article-title":"Stability of naive and memory phenotypes on resting CD4 Tcells in vivo","volume":"162","author":"Boursalian T. E.","year":"1999","journal-title":"J. Immunol."},{"key":"p_6","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90077-2"},{"key":"p_7","doi-asserted-by":"crossref","unstructured":"Buckton K. E. Court Brown W. M. & Smith P. G. 1967 Lymphocyte survival in men treated with X-rays for ankylosing spondylitis. Nature 214 470^473.","DOI":"10.1038\/214470a0"},{"key":"p_8","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.151.12.6657","article-title":"Unexpected expansions of CD8-bearing cells in old mice","volume":"151","author":"Callahan J. E.","year":"1993","journal-title":"J. Immunol."},{"key":"p_9","doi-asserted-by":"crossref","unstructured":"Callan M. F. Steven N. Krausa P. Wilson J. D. Moss P. A. Gillespie G. M. Bell J. I. ickinson A. B. & McMichael A. J. 1996 Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nature Med. 2 906^911.","DOI":"10.1038\/nm0896-906"},{"key":"p_10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.9.1395"},{"key":"p_11","doi-asserted-by":"crossref","unstructured":"Chambers C. A. Sullivan T. J. & Allison J. P. 1997 Lymphoproliferation in CTLA-4-de\u00a2cient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7 885^895.","DOI":"10.1016\/S1074-7613(00)80406-9"},{"key":"p_12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830221025"},{"key":"p_13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1996.tb00694.x"},{"key":"p_14","article-title":"Di\u00a1erent susceptibility of cytotoxic T cells to CD95 (Fas\/Apo-1) ligand-mediated cell death after activation in vitro versus in vivo","volume":"156","author":"Ehl S.","year":"1996","journal-title":"J. Immunol."},{"key":"p_15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.163.2.270"},{"key":"p_16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.9.1407"},{"key":"p_17","doi-asserted-by":"crossref","unstructured":"Hastie N. D. Dempster M. Dunlop M. G. Thompson A. M. Green D. K. & Allshire . C. 1990 Telomere reduction in human colorectal carcinoma and with aging. Nature 346 866^868.","DOI":"10.1038\/346866a0"},{"key":"p_18","first-page":"89","article-title":"Direct measurement of T Iymphocyte kinetics in humans using a stable isotope-mass spectrometric technique: e\u00a1ects of HIV-1 infection and antiretroviral therapy","volume":"5","author":"Hellerstein M.","year":"1999","journal-title":"Nature Med."},{"key":"p_19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1997.tb01034.x"},{"key":"p_20","doi-asserted-by":"crossref","unstructured":"Lundblad V. & Wright W. E. 1996 Telomeres and telomerase: a simple picture becomes complex. Cell 87 369^375.","DOI":"10.1016\/S0092-8674(00)81358-6"},{"key":"p_21","doi-asserted-by":"crossref","unstructured":"Macallan D. C. Fullerton C. A. Neese . Haddock K. Park S. & Hellerstein M. K. 1998 Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro in animals and in humans. Proc. Natl Acad. Sci. 95 708^713.","DOI":"10.1073\/pnas.95.2.708"},{"key":"p_22","doi-asserted-by":"crossref","unstructured":"McHeyzer-Williams M. G. & Davis M. M. 1995 Antigenspeci\u00a2c development of primary and memory T cells in vivo. Science 268 106^111.","DOI":"10.1126\/science.7535476"},{"key":"p_23","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.156.12.4609","article-title":"Thymic-independent T cell regeneration occurs via antigen driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing","volume":"156","author":"Mackall C. L.","year":"1996","journal-title":"J. Immunol."},{"key":"p_24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.171.3.801"},{"key":"p_25","doi-asserted-by":"crossref","unstructured":"McLean A. & Michie C. A. 1995 In vivo estimates of division and death rates of human T Iymphocytes. Proc. Natl Acad. Sci. 92 3797^3711.","DOI":"10.1073\/pnas.92.9.3707"},{"key":"p_26","doi-asserted-by":"crossref","unstructured":"Maini M. K. Wedderburn L. . Hall F. C. Wack A. Casorati G. & Beverley P. C. L. 1998 A comparison of two techniques for the molecular tracking of speci\u00a2c T-cell responses: CD4+ T-cell clones persist in a stable hierarchy but at a lower frequency than clones in the CD8+ population. Immunology 94 529^535.","DOI":"10.1046\/j.1365-2567.1998.00556.x"},{"key":"p_27","doi-asserted-by":"crossref","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 M. K.","year":"1999","journal-title":"J. Immunol."},{"key":"p_28","unstructured":"Maini M. K. Gudgeon G. Wedderburn L. . ickinson A. B. & Beverley P. C. L. 2000 Global longitudinal molecular analysis of clonality in CD4 and CD8 T cells in EBV infection. (In preparation.)"},{"key":"p_29","doi-asserted-by":"crossref","unstructured":"Masuko K. Kato T. Ikeda Y. Okubo M. Mizushima Y. Nishioka K. & Yamamoto K. 1994 Dynamic changes of accumulated T cell clonotypes during antigenic stimulation in vivo and in vitro. Int. Immunol. 6 1959^1966.","DOI":"10.1093\/intimm\/6.12.1959"},{"key":"p_30","first-page":"59","article-title":"Evidence for di\u00a1erential expression of CD45 isoforms by precursors for memory-dependent and independent cytotoxic responses: human CD8 memory CTLp selectively express CD45 O (UCHL1)","volume":"1","author":"Merkenschlager M.","year":"1990","journal-title":"Int. Immunol"},{"key":"p_31","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830181102"},{"key":"p_32","doi-asserted-by":"crossref","unstructured":"Michie C. A. McLean A. Alcock C. & Beverley P. C. L. 1992 Lifespan of human Iymphocyte subsets de\u00a2ned by CD45 isoforms. Nature 360 264^265.","DOI":"10.1038\/360264a0"},{"key":"p_33","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.1.17"},{"key":"p_34","doi-asserted-by":"crossref","unstructured":"Murali-Krishna K. Altman J. D. Suresh M. Sourdive D. J. D. Zajac A. J. Miller J. D. Slansky J. & Ahmed . 1998 Counting antigen-speci\u00a2c CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8 177^187.","DOI":"10.1016\/S1074-7613(00)80470-7"},{"key":"p_35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1997.tb01025.x"},{"key":"p_36","doi-asserted-by":"crossref","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 D. N.","year":"1994","journal-title":"J. Exp. Med."},{"key":"p_37","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.158.9.4493","article-title":"Expanded CD4+ and CD8+ T cell clones in elderly humans","volume":"158","author":"Schwab","year":"1997","journal-title":"J. Immunol."},{"key":"p_38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.6.1933"},{"key":"p_39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.5.1815"},{"key":"p_40","doi-asserted-by":"crossref","unstructured":"Singer G. G. & Abbas A. K. 1994 The fas antigen is involved in peripheral but not thymic deletion of T Iymphocytes in T cell receptor transgenic mice. Immunity 1 365^371.","DOI":"10.1016\/1074-7613(94)90067-1"},{"key":"p_41","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830241102"},{"key":"p_42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.174.3.717"},{"key":"p_43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1997.tb00960.x"},{"key":"p_44","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80306-4"},{"key":"p_45","doi-asserted-by":"crossref","unstructured":"Tough D. F. Borrow P. & Sprent J. 1996 Induction of bystander T cell proliferation by viruses and type 1 interferon in vivo. Science 272 1947^1950.","DOI":"10.1126\/science.272.5270.1947"},{"key":"p_46","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.4.1127"},{"key":"p_47","article-title":"Loss of telomeric DNA during aging of normal and trisomy-21 human","volume":"52","author":"Vaziri H.","year":"1993","journal-title":"Iymphocytes. Am. J. Hum. Genet."},{"key":"p_48","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(96)00114-7"},{"key":"p_49","doi-asserted-by":"crossref","unstructured":"Wack A. Cossarizza A. Heltai S. Barbietri D. D'Addato S. Fransceschi C. Dellabona P. & Casorati G. 1998 Agerelated modi\u00a2cations of the human ab T cell repertoire due to di\u00a1erent clonal expansions in the CD4+ and CD8+ subsets. Int. Immunol. 10 1281^1288.","DOI":"10.1093\/intimm\/10.9.1281"},{"key":"p_50","doi-asserted-by":"crossref","unstructured":"Wedderburn L. . O'Hehir . E. Hewitt C. . A. Lamb J. . & Owen M. J. 1993 In-vivo clonal dominance and limited T-cell receptor usage in human CD4(+) T-cell recognition of house dust mite allergens. Proc. Natl Acad. Sci. 90 8214^8218.","DOI":"10.1073\/pnas.90.17.8214"},{"key":"p_51","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.6.2471"},{"key":"p_52","doi-asserted-by":"crossref","unstructured":"Weng N. P. Granger L. & Hodes . J. 1997 Telomere lengthening and telomerase activation during human B cell di\u00a1erentiation. Proc. Natl Acad. Sci. 94 10 827^10 832.","DOI":"10.1073\/pnas.94.20.10827"},{"key":"p_53","doi-asserted-by":"crossref","unstructured":"Young A. J. & Hay J. B. 1995 apid turnover of the recirculating pool in vivo. Int. Immunol. 7 1607^1615.","DOI":"10.1093\/intimm\/7.10.1607"},{"key":"p_54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.4.1367"},{"key":"p_55","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830261215"}],"container-title":["Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2000.0580","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2000.0580","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:26:22Z","timestamp":1778621182000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rstb\/article\/355\/1395\/401-406\/19590"}},"subtitle":[],"editor":[{"given":"A. J.","family":"McMichael","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"P. C.","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2000,3,29]]},"references-count":55,"journal-issue":{"issue":"1395","published-print":{"date-parts":[[2000,3,29]]}},"alternative-id":["10.1098\/rstb.2000.0580"],"URL":"https:\/\/doi.org\/10.1098\/rstb.2000.0580","relation":{},"ISSN":["0962-8436","1471-2970"],"issn-type":[{"value":"0962-8436","type":"print"},{"value":"1471-2970","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3,29]]}}}