Skip to main content
SpringerLink
Log in

Large Numbers of Dysfunctional CD8+ T Lymphocytes Bearing Receptors for a Single Dominant CMV Epitope in the Very Old

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Longitudinal studies suggest that a set of immune parameters including high percentages of peripheral CD8+, CD28−, CD57+ T lymphocytes, low CD4 and B cell counts, and poor T cell proliferative responses to mitogens is associated with decreased remaining longevity in the free-living very elderly (>85 years). This combination of immune parameters was also significantly associated with an inverted CD4/CD8 ratio and cytomegalovirus seropositivity. Here, using tetramer technology, we show markedly increased numbers of CD8+ T cells bearing receptors for one single CMV epitope in the very elderly. Moreover, the fraction of these tetramer-reactive cells secreting interferon-γ after specific antigenic stimulation was significantly lower in the old than in the young, as was the percentage of CD28-positive cells in this population. Therefore, we conclude that marked expansions of CMV-specific CD8+ T cells have occurred and that the obsession of a large fraction of the entire CD8+ T cell subset with one single viral epitope may contribute to the increased incidence of infectious disease in the elderly by shrinking the T cell repertoire available for responses to other antigens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wikby A, Johansson B, Ferguson F, Olsson J: Age-related changes in immune parameters in a very old population of Swedish people: A longitudinal study. Exp Gerontol 29:531–541, 1994

    Google Scholar 

  2. Ferguson FG, Wikby A, Maxson P, Olsson J, Johansson B: Immune parameters in a longitudinal study of a very old population of Swedish people: A comparison between survivors and nonsurvivors. J Gerontol Biol Sci 50(A):B378–B382, 1995

    Google Scholar 

  3. Wikby A, Johansson B, Olsson J, Löfgren S, Nilsson B-O, Ferguson FG: Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: The Swedish NONA immune study. Exp Gerontol 37:445–453, 2002

    Google Scholar 

  4. Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG: Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: The Swedish longitudinal OCTO-immune study. Mech Ageing Dev 102:187–198, 1998

    Google Scholar 

  5. Olsson J, Wikby A, Johansson B, Löfgren S, Nilsson B-O, Ferguson FG: Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: The Swedish longitudinal OCTO immune study. Mech Ageing Dev 121:187–201, 2000

    Google Scholar 

  6. Looney RJ, Falsey A, Campbell D, Torres A, Kolassa J, Brower C, McCann R, Menegus M, McCormick K, Frampton M, Hall W, Abraham GN: Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin. Immunol. 90:213–219, 1999

    Google Scholar 

  7. Merino J, Martinez-Gonzalez MA, Rubio M, Inoges S, Sanchez-Ibarrola A, Subira ML: Progressive decrease of CD8high+ CD28+ CD57- cells with ageing. Clin Exp Immunol 112:48–51, 1998

    Google Scholar 

  8. Fagnoni F, Vescovini R, Mayyola M, Bologna G, Nigro E, Lavgetto G, Franceshi C, Passeri M, Sansoni P: Expansion of cytotoxic CD8+CD28- T cells in healthy aging people, including centenatians. Immunology 88:501–507, 1996

    Google Scholar 

  9. Wack A, Cossarizza A, Heltai S, Barbieri D, D'Addato S, Fransceschi C, Dellabona P, Casorati G: Age-related modifications of the human alphabeta T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets. Int Immunol 10:1281–1288, 1998

    Google Scholar 

  10. Posnett DN, Edinger JW, Manavalan JS, Irwin C, Marodon G: Differentiation of human CD8 T cells: Implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. Int Immunol 11:229–241, 1999

    Google Scholar 

  11. Borysiewicz L, Hickling J, Graham S, Sinclair J, Cranage M, Smith G, Sissons J: Human-specific cytotoxic T cells. Relative frequency of stage-specific CTL recognizing the 72–KD immediate early protein and glycoprotein B expressed by recombinant vaccinia viruses. J Exp Med 168:919–931, 1988

    Google Scholar 

  12. Gillespie GM, Wills MR, Appay V, O'Callaghan C, Murphy M, Smith N, Sissons P, Rowland-Jones S, Bell JI, Moss PA: Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8+ T lymphocytes in health seropositive donors. J Virol 74:8140–8150, 2000

    Google Scholar 

  13. Gamadia LE, Rentenaar RJ, Baars PA, Remmerswaal EB, Surachno S, Weel JF, Toebes M, Schumacher TN, ten Berge IJ, van Lier RA: Differentiation of cytomegalovirus-specific CD8(+) T cells in healthy and immunosuppressed virus carriers. Blood 98:754–761, 2001

    Google Scholar 

  14. Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, Sissons JG: The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: Frequency, specificity, and T-cell receptor usage of pp65–specific CTL. J Virol 70(11):7569–7579, 1996

    Google Scholar 

  15. Solache A, Morgan C, Dodi A, Morte C, Scott I, Baboonian C, Zal B, Goldman J, Grundy J, Madrigal JA: Identification of three HLA-A*0201–restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus. J Immunol 163:5512–5518, 1999

    Google Scholar 

  16. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA: Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169:1984–1992, 2002

    Google Scholar 

  17. Gratama JW, Naipal AM, Osterveer MA, Stijnen T, Kluin-Nelemans HC, Ginsel LA, den Ottolander GJ, Heckker AC, Damaro J, van der Giesen M, Tanke HJ: Effects of herpes virus carrier status on peripheral T lymphocyte subsets. Blood 70:516–523, 1987

    Google Scholar 

  18. Altman J, Moss P, Goulder P, Barouch D, McHeyzer-Williams M, Bell J, McMichael A, Davis M: Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96, 1996

    Google Scholar 

  19. Mayer S, Scheibenbogen C, Lee KH, Keilholz W, Stevanovic S, Rammensee HG, Keilholz U: A sensitive proliferation assay to determine the specific T cell response against HLA-A2.1–binding peptides. J Immunol Methods 197:131–137, 1996

    Google Scholar 

  20. Callahan JE, Kappler JW, Marrack P: Unexpected expansions of CD8–bearing cells in old mice. J Immunol 151:6657–6669, 1993

    Google Scholar 

  21. Nilsson B-O, Ernerudh J, Johansson B, Evrin PE, Löfgren S, Ferguson F, Wikby A: Morbidity does not influence the T-cell immune risk phenotype in the elderly: Findings in the Swedish NONA immune study using sample selection protocols. Mech Ageing Dev 124:469–476, 2003

    Google Scholar 

  22. Weekes MP, Carmichael AJ, Wills MR, Mynard K, Sissons JG: Human CD28-CD8+ T cells contain greatly expanded functional virus-specific memory CTL clones. J Immunol 162:7569–7577, 1999

    Google Scholar 

  23. Weekes MP, Wills MR, Mynard K, Carmichael AJ, Sissons JG: The memory cytotoxic T-lymphocyte (CTL) response to human cytomegalovirus infection contains individual peptide-specific CTL clones that have undergone extensive expansion in vivo. J Virol 73:2099–2108, 1999

    Google Scholar 

  24. van Baarle D, Hovenkamp E, Callan MF, Wolthers KC, Kostense S, Tan LC, Niesters HG, Osterhaus AD, McMichael AJ, van Oers MH, Miedema F: Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma. Blood 98:146–155, 2001

    Google Scholar 

  25. Kostense S, Ogg GS, Manting EH, Gillespie G, Joling J, Vandenberghe K, Veenhof E Z, van Baarle D, Jurriaans S, Klein MR, Miedema F: High viral burden in the presence of major HIV-specific CD8(+) T cell expansions: Evidence for impaired CTL effector function. Eur J Immunol 31:677–686, 2001

    Google Scholar 

  26. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD: Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512, 2000

    Google Scholar 

  27. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM: Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677–685, 1999

    Google Scholar 

  28. Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M: Biomarkers of immunosenescence within an evolutionary perspective: The challenge of heterogeneity and the role of antigenic load. Exp Gerontol 34:911–921, 1999

    Google Scholar 

  29. Hyland P, Barnett C, Pawelec G, Barnett Y: Age-related accumulation of oxidative DNA damage and alterations in levels of p16(INK4a/CDKN2a), p21(WAF1/CIP1/SDI1) and p27(KIP1) in human CD4+ T cell clones in vitro. Mech Ageing Dev 122:1151–1167, 2001

    Google Scholar 

  30. Spaulding C, Guo W, Effros RB: Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34:633–644, 1999

    Google Scholar 

  31. Brehm MA, Pinto AK, Daniels KA, Schneck JP, Welsh RM, Selin LK: T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nat Immunol 3: 627–634, 2002

    Google Scholar 

  32. Hiemstra HS, Schloot NC, van Veelen PA, Willemen SJ, Franken KL, van Rood JJ, de Vries RR, Chaudhuri A, Behan PO, Drijfhout JW, Roep BO: Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase. Proc Natl Acad Sci USA 98:3988–3991, 2001

    Google Scholar 

  33. Klenerman P, Zinkernagel RM: Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394:482–485, 1998

    Google Scholar 

  34. McLeod JD: Apoptotic capability in ageing T cells. Mech Ageing Dev 121:151–159, 2000

    Google Scholar 

  35. Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F: 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. Exp Gerontol 29:601–609, 1994

    Google Scholar 

  36. Nociari MM, Telford W, Russo C: Postthymic development of CD28-CD8+ T cell subset: Age-associated expansion and shift from memory to naive phenotype. J Immunol 162:3327–3335, 1999

    Google Scholar 

  37. Pawelec G, Hirokawa K, Fülöp T: Altered T cell signalling in ageing. Mech Ageing Dev 122:1613–1637, 2001

    Google Scholar 

  38. Tortorella C, Loria MP, Piazzolla G, Schulzekoops H, Lipsky PE, Jirillo E, Antonaci S: Age-related impairment of T cell proliferative responses related to the decline of CD28+ T cell subsets. Arch. Gerontol. Geriatr 26:55–70, 1997

    Google Scholar 

  39. Pawelec G: Hypothesis: Loss of telomerase inducibility and subsequent replicative senescence in cultured human T cells is a result of altered costimulation. Mech Ageing Dev 121:181–185, 2000

    Google Scholar 

  40. Effros RB: Costimulatory mechanisms in the elderly. Vaccine 18:1661–1665, 2000

    Google Scholar 

  41. Weng NP, Levine BL, June CH, Hodes RJ: Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183:2471–2479, 1996

    Google Scholar 

  42. Aubert G, Hassan-Walker AF, Madrigal JA, Emery VC, Morte C, Grace S, Koh MB, Potter M, Prentice HG, Dodi IA, Travers PJ: Cytomegalovirus-specific cellular immune responses and viremia in recipients of allogeneic stem cell transplants. J Infect Dis 184:955–963, 2001

    Google Scholar 

  43. Franceschi C, Bonafe M, Valensin S: Human immunosenescence: The prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18:1717–1720, 2000

    Google Scholar 

  44. Ouyang Q, Wagner WM, Walter S, Müller CA, Wikby A, Aubert G, Klatt T, Stevanovic S, Dodi T, Pawelec G: An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein-Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness. Mech Ageing Dev 124:477–485, 2003

    Google Scholar 

  45. Zhou T, Edwards CK, Mountz JD: Prevention of age-related T cell apoptosis defect in CD2–fas-transgenic mice. J Exp Med 182:129–137, 1995

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Tuebingen Ageing and Tumour Immunology Group, Section for Transplantation-Immunology and Immunohematology, University of Tübingen, Tübingen, Germany

    Qin Ouyang, Wolfgang M. Wagner & Graham Pawelec

  2. Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Jönköping, Sweden

    Anders Wikby

  3. Department of Immunology, University of Tübingen, Tübingen, Germany

    Steffen Walter

  4. Anthony Nolan Research Institute, Royal Free and University College Medical School, London, United Kingdom

    Geraldine Aubert, Anthony I. Dodi & Paul Travers

Authors
  1. Qin Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wolfgang M. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anders Wikby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steffen Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geraldine Aubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anthony I. Dodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul Travers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Graham Pawelec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qin Ouyang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ouyang, Q., Wagner, W.M., Wikby, A. et al. Large Numbers of Dysfunctional CD8+ T Lymphocytes Bearing Receptors for a Single Dominant CMV Epitope in the Very Old. J Clin Immunol 23, 247–257 (2003). https://doi.org/10.1023/A:1024580531705

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1024580531705

Search

Navigation