Skip to main content
NCBI home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Mar 29;355(1395):391–400. doi: 10.1098/rstb.2000.0579

T-cell memory: lessons from Epstein-Barr virus infection in man.

A B Rickinson 1, M F Callan 1, N E Annels 1
PMCID: PMC1692739  PMID: 10794060

Abstract

Epstein-Barr virus offers an ideal opportunity to follow the human T-cell response to a virus infection over time from its acute primary phase, as seen in infectious mononucleosis patients, into the memory phase that accompanies life-long virus persistence. Here we review recent evidence on the development and maturation of cytotoxic T-cell memory using this viral system.

Full Text

The Full Text of this article is available as a PDF (182.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akbar A. N., Borthwick N., Salmon M., Gombert W., Bofill M., Shamsadeen N., Pilling D., Pett S., Grundy J. E., Janossy G. 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. J Exp Med. 1993 Aug 1;178(2):427–438. doi: 10.1084/jem.178.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akbar A. N., Terry L., Timms A., Beverley P. C., Janossy G. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol. 1988 Apr 1;140(7):2171–2178. [PubMed] [Google Scholar]
  3. Altman J. D., Moss P. A., Goulder P. J., Barouch D. H., McHeyzer-Williams M. G., Bell J. I., McMichael A. J., Davis M. M. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996 Oct 4;274(5284):94–96. doi: 10.1126/science.274.5284.94. [DOI] [PubMed] [Google Scholar]
  4. Argaet V. P., Schmidt C. W., Burrows S. R., Silins S. L., Kurilla M. G., Doolan D. L., Suhrbier A., Moss D. J., Kieff E., Sculley T. B. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus. J Exp Med. 1994 Dec 1;180(6):2335–2340. doi: 10.1084/jem.180.6.2335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Azuma M., Phillips J. H., Lanier L. L. CD28- T lymphocytes. Antigenic and functional properties. J Immunol. 1993 Feb 15;150(4):1147–1159. [PubMed] [Google Scholar]
  6. Babcock G. J., Decker L. L., Freeman R. B., Thorley-Lawson D. A. Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J Exp Med. 1999 Aug 16;190(4):567–576. doi: 10.1084/jem.190.4.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blake N., Lee S., Redchenko I., Thomas W., Steven N., Leese A., Steigerwald-Mullen P., Kurilla M. G., Frappier L., Rickinson A. Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. Immunity. 1997 Dec;7(6):791–802. doi: 10.1016/s1074-7613(00)80397-0. [DOI] [PubMed] [Google Scholar]
  8. Bogedain C., Wolf H., Modrow S., Stuber G., Jilg W. Specific cytotoxic T lymphocytes recognize the immediate-early transactivator Zta of Epstein-Barr virus. J Virol. 1995 Aug;69(8):4872–4879. doi: 10.1128/jvi.69.8.4872-4879.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burrows S. R., Gardner J., Khanna R., Steward T., Moss D. J., Rodda S., Suhrbier A. Five new cytotoxic T cell epitopes identified within Epstein-Barr virus nuclear antigen 3. J Gen Virol. 1994 Sep;75(Pt 9):2489–2493. doi: 10.1099/0022-1317-75-9-2489. [DOI] [PubMed] [Google Scholar]
  10. Burrows S. R., Khanna R., Burrows J. M., Moss D. J. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease. J Exp Med. 1994 Apr 1;179(4):1155–1161. doi: 10.1084/jem.179.4.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Burrows S. R., Sculley T. B., Misko I. S., Schmidt C., Moss D. J. An Epstein-Barr virus-specific cytotoxic T cell epitope in EBV nuclear antigen 3 (EBNA 3). J Exp Med. 1990 Jan 1;171(1):345–349. doi: 10.1084/jem.171.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Burrows S. R., Silins S. L., Khanna R., Burrows J. M., Rischmueller M., McCluskey J., Moss D. J. Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur J Immunol. 1997 Jul;27(7):1726–1736. doi: 10.1002/eji.1830270720. [DOI] [PubMed] [Google Scholar]
  13. Busch D. H., Pilip I., Pamer E. G. Evolution of a complex T cell receptor repertoire during primary and recall bacterial infection. J Exp Med. 1998 Jul 6;188(1):61–70. doi: 10.1084/jem.188.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Callan M. F., Annels N., Steven N., Tan L., Wilson J., McMichael A. J., Rickinson A. B. T cell selection during the evolution of CD8+ T cell memory in vivo. Eur J Immunol. 1998 Dec;28(12):4382–4390. doi: 10.1002/(SICI)1521-4141(199812)28:12<4382::AID-IMMU4382>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  15. Callan M. F., Steven N., Krausa P., Wilson J. D., Moss P. A., Gillespie G. M., Bell J. I., Rickinson A. B., McMichael A. J. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med. 1996 Aug;2(8):906–911. doi: 10.1038/nm0896-906. [DOI] [PubMed] [Google Scholar]
  16. Callan M. F., Tan L., Annels N., Ogg G. S., Wilson J. D., O'Callaghan C. A., Steven N., McMichael A. J., Rickinson A. B. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med. 1998 May 4;187(9):1395–1402. doi: 10.1084/jem.187.9.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Campos-Lima P. O., Levitsky V., Imreh M. P., Gavioli R., Masucci M. G. Epitope-dependent selection of highly restricted or diverse T cell receptor repertoires in response to persistent infection by Epstein-Barr virus. J Exp Med. 1997 Jul 7;186(1):83–89. doi: 10.1084/jem.186.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Couedel C., Bodinier M., Peyrat M. A., Bonneville M., Davodeau F., Lang F. Selection and long-term persistence of reactive CTL clones during an EBV chronic response are determined by avidity, CD8 variable contribution compensating for differences in TCR affinities. J Immunol. 1999 Jun 1;162(11):6351–6358. [PubMed] [Google Scholar]
  19. Gallimore A., Glithero A., Godkin A., Tissot A. C., Plückthun A., Elliott T., Hengartner H., Zinkernagel R. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med. 1998 May 4;187(9):1383–1393. doi: 10.1084/jem.187.9.1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gavioli R., Kurilla M. G., de Campos-Lima P. O., Wallace L. E., Dolcetti R., Murray R. J., Rickinson A. B., Masucci M. G. Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4. J Virol. 1993 Mar;67(3):1572–1578. doi: 10.1128/jvi.67.3.1572-1578.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hamann D., Baars P. A., Rep M. H., Hooibrink B., Kerkhof-Garde S. R., Klein M. R., van Lier R. A. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997 Nov 3;186(9):1407–1418. doi: 10.1084/jem.186.9.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hou S., Hyland L., Ryan K. W., Portner A., Doherty P. C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature. 1994 Jun 23;369(6482):652–654. doi: 10.1038/369652a0. [DOI] [PubMed] [Google Scholar]
  23. Kalams S. A., Johnson R. P., Dynan M. J., Hartman K. E., Harrer T., Harrer E., Trocha A. K., Blattner W. A., Buchbinder S. P., Walker B. D. T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant. J Exp Med. 1996 Apr 1;183(4):1669–1679. doi: 10.1084/jem.183.4.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med. 1992 Jul 1;176(1):169–176. doi: 10.1084/jem.176.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lehner P. J., Wang E. C., Moss P. A., Williams S., Platt K., Friedman S. M., Bell J. I., Borysiewicz L. K. Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment. J Exp Med. 1995 Jan 1;181(1):79–91. doi: 10.1084/jem.181.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Levitskaya J., Coram M., Levitsky V., Imreh S., Steigerwald-Mullen P. M., Klein G., Kurilla M. G., Masucci M. G. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature. 1995 Jun 22;375(6533):685–688. doi: 10.1038/375685a0. [DOI] [PubMed] [Google Scholar]
  27. Levitsky V., Zhang Q. J., Levitskaya J., Masucci M. G. The life span of major histocompatibility complex-peptide complexes influences the efficiency of presentation and immunogenicity of two class I-restricted cytotoxic T lymphocyte epitopes in the Epstein-Barr virus nuclear antigen 4. J Exp Med. 1996 Mar 1;183(3):915–926. doi: 10.1084/jem.183.3.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levitsky V., de Campos-Lima P. O., Frisan T., Masucci M. G. The clonal composition of a peptide-specific oligoclonal CTL repertoire selected in response to persistent EBV infection is stable over time. J Immunol. 1998 Jul 15;161(2):594–601. [PubMed] [Google Scholar]
  29. Lin M. Y., Welsh R. M. Stability and diversity of T cell receptor repertoire usage during lymphocytic choriomeningitis virus infection of mice. J Exp Med. 1998 Dec 7;188(11):1993–2005. doi: 10.1084/jem.188.11.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. McHeyzer-Williams M. G., Davis M. M. Antigen-specific development of primary and memory T cells in vivo. Science. 1995 Apr 7;268(5207):106–111. doi: 10.1126/science.7535476. [DOI] [PubMed] [Google Scholar]
  31. Misko I. S., Cross S. M., Khanna R., Elliott S. L., Schmidt C., Pye S. J., Silins S. L. Crossreactive recognition of viral, self, and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes: implications for molecular mimicry in autoimmune disease. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2279–2284. doi: 10.1073/pnas.96.5.2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Moss D. J., Rickinson A. B., Pope J. H. Long-term T-cell-mediated immunity to Epstein-Barr virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive donor leukocytes. Int J Cancer. 1978 Dec;22(6):662–668. doi: 10.1002/ijc.2910220604. [DOI] [PubMed] [Google Scholar]
  33. Moss P. A., Moots R. J., Rosenberg W. M., Rowland-Jones S. J., Bodmer H. C., McMichael A. J., Bell J. I. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8987–8990. doi: 10.1073/pnas.88.20.8987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Murray R. J., Kurilla M. G., Brooks J. M., Thomas W. A., Rowe M., Kieff E., Rickinson A. B. Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med. 1992 Jul 1;176(1):157–168. doi: 10.1084/jem.176.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nixon D. F., McMichael A. J. Cytotoxic T-cell recognition of HIV proteins and peptides. AIDS. 1991 Sep;5(9):1049–1059. [PubMed] [Google Scholar]
  36. Pantaleo G., Soudeyns H., Demarest J. F., Vaccarezza M., Graziosi C., Paolucci S., Daucher M., Cohen O. J., Denis F., Biddison W. E. Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9848–9853. doi: 10.1073/pnas.94.18.9848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pichler W. J., Mauri-Hellweg D., Baumann K., Bettens F. Selective expression of T-cell receptor-V beta in acute infectious mononucleosis. Arch Intern Med. 1995 Jul 24;155(14):1555–1556. [PubMed] [Google Scholar]
  38. Posnett D. N., Edinger J. W., Manavalan J. S., Irwin C., Marodon G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. Int Immunol. 1999 Feb;11(2):229–241. doi: 10.1093/intimm/11.2.229. [DOI] [PubMed] [Google Scholar]
  39. Reinherz E. L., O'Brien C., Rosenthal P., Schlossman S. F. The cellular basis for viral-induced immunodeficiency: analysis by monoclonal antibodies. J Immunol. 1980 Sep;125(3):1269–1274. [PubMed] [Google Scholar]
  40. Rickinson A. B., Moss D. J. Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol. 1997;15:405–431. doi: 10.1146/annurev.immunol.15.1.405. [DOI] [PubMed] [Google Scholar]
  41. Scotet E., David-Ameline J., Peyrat M. A., Moreau-Aubry A., Pinczon D., Lim A., Even J., Semana G., Berthelot J. M., Breathnach R. T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis. J Exp Med. 1996 Nov 1;184(5):1791–1800. doi: 10.1084/jem.184.5.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sheldon P. J., Hemsted E. H., Papamichail M., Holborow E. J. Thymic origin of atypical lymphoid cells in infectious mononucleosis. Lancet. 1973 May 26;1(7813):1153–1155. doi: 10.1016/s0140-6736(73)91148-3. [DOI] [PubMed] [Google Scholar]
  43. Silins S. L., Cross S. M., Elliott S. L., Pye S. J., Burrows J. M., Moss D. J., Misko I. S. Selection of a diverse TCR repertoire in response to an Epstein-Barr virus-encoded transactivator protein BZLF1 by CD8+ cytotoxic T lymphocytes during primary and persistent infection. Int Immunol. 1997 Nov;9(11):1745–1755. doi: 10.1093/intimm/9.11.1745. [DOI] [PubMed] [Google Scholar]
  44. Silins S. L., Cross S. M., Elliott S. L., Pye S. J., Burrows S. R., Burrows J. M., Moss D. J., Argaet V. P., Misko I. S. Development of Epstein-Barr virus-specific memory T cell receptor clonotypes in acute infectious mononucleosis. J Exp Med. 1996 Nov 1;184(5):1815–1824. doi: 10.1084/jem.184.5.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Smith T. J., Terada N., Robinson C. C., Gelfand E. W. Acute infectious mononucleosis stimulates the selective expression/expansion of V beta 6.1-3 and V beta 7 T cells. Blood. 1993 Mar 15;81(6):1521–1526. [PubMed] [Google Scholar]
  46. Steven N. M., Annels N. E., Kumar A., Leese A. M., Kurilla M. G., Rickinson A. B. Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J Exp Med. 1997 May 5;185(9):1605–1617. doi: 10.1084/jem.185.9.1605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Steven N. M., Leese A. M., Annels N. E., Lee S. P., Rickinson A. B. Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J Exp Med. 1996 Nov 1;184(5):1801–1813. doi: 10.1084/jem.184.5.1801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Strang G., Rickinson A. B. In vitro expansion of Epstein-Barr virus-specific HLA-restricted cytotoxic T cells direct from the blood of infectious mononucleosis patients. Immunology. 1987 Dec;62(4):647–654. [PMC free article] [PubMed] [Google Scholar]
  49. Strang G., Rickinson A. B. Multiple HLA class I-dependent cytotoxicities constitute the "non-HLA-restricted" response in infectious mononucleosis. Eur J Immunol. 1987 Jul;17(7):1007–1013. doi: 10.1002/eji.1830170717. [DOI] [PubMed] [Google Scholar]
  50. Sutkowski N., Palkama T., Ciurli C., Sekaly R. P., Thorley-Lawson D. A., Huber B. T. An Epstein-Barr virus-associated superantigen. J Exp Med. 1996 Sep 1;184(3):971–980. doi: 10.1084/jem.184.3.971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Svedmyr E., Jondal M. Cytotoxic effector cells specific for B Cell lines transformed by Epstein-Barr virus are present in patients with infectious mononucleosis. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1622–1626. doi: 10.1073/pnas.72.4.1622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tan L. C., Gudgeon N., Annels N. E., Hansasuta P., O'Callaghan C. A., Rowland-Jones S., McMichael A. J., Rickinson A. B., Callan M. F. A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol. 1999 Feb 1;162(3):1827–1835. [PubMed] [Google Scholar]
  53. Tierney R. J., Steven N., Young L. S., Rickinson A. B. Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol. 1994 Nov;68(11):7374–7385. doi: 10.1128/jvi.68.11.7374-7385.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tomkinson B. E., Maziarz R., Sullivan J. L. Characterization of the T cell-mediated cellular cytotoxicity during acute infectious mononucleosis. J Immunol. 1989 Jul 15;143(2):660–670. [PubMed] [Google Scholar]
  55. Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
  56. Yao Q. Y., Rickinson A. B., Gaston J. S., Epstein M. A. In vitro analysis of the Epstein-Barr virus: host balance in long-term renal allograft recipients. Int J Cancer. 1985 Jan 15;35(1):43–49. doi: 10.1002/ijc.2910350108. [DOI] [PubMed] [Google Scholar]
  57. Zajac A. J., Blattman J. N., Murali-Krishna K., Sourdive D. J., Suresh M., Altman J. D., Ahmed R. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998 Dec 21;188(12):2205–2213. doi: 10.1084/jem.188.12.2205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. d'Angeac A. D., Monier S., Pilling D., Travaglio-Encinoza A., Rème T., Salmon M. CD57+ T lymphocytes are derived from CD57- precursors by differentiation occurring in late immune responses. Eur J Immunol. 1994 Jul;24(7):1503–1511. doi: 10.1002/eji.1830240707. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES