Skip to main content
PMC home page
Immunology logoLink to Immunology
. 1996 Aug;88(4):501–507. doi: 10.1046/j.1365-2567.1996.d01-689.x

Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians.

F F Fagnoni 1, R Vescovini 1, M Mazzola 1, G Bologna 1, E Nigro 1, G Lavagetto 1, C Franceschi 1, M Passeri 1, P Sansoni 1
PMCID: PMC1456634  PMID: 8881749

Abstract

Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of CD28 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of CD28- T cells in percentage and absolute number, predominantly among CD8+ T cells. CD28- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing CD25, CD38, CD69, CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated CD2 and CD11a; CD62L absent). At the functional level, freshly isolated purified CD28- CD8+ T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8+ CD28- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin.

Full text

PDF
501

Selected References

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

  1. Azuma M., Cayabyab M., Buck D., Phillips J. H., Lanier L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J Exp Med. 1992 Feb 1;175(2):353–360. doi: 10.1084/jem.175.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Bell E. B., Sparshott S. M. Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 1990 Nov 8;348(6297):163–166. doi: 10.1038/348163a0. [DOI] [PubMed] [Google Scholar]
  4. Borthwick N. J., Bofill M., Gombert W. M., Akbar A. N., Medina E., Sagawa K., Lipman M. C., Johnson M. A., Janossy G. Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28- T cells. AIDS. 1994 Apr;8(4):431–441. doi: 10.1097/00002030-199404000-00004. [DOI] [PubMed] [Google Scholar]
  5. Bretscher P. The two-signal model of lymphocyte activation twenty-one years later. Immunol Today. 1992 Feb;13(2):74–76. doi: 10.1016/0167-5699(92)90138-W. [DOI] [PubMed] [Google Scholar]
  6. Brinchmann J. E., Dobloug J. H., Heger B. H., Haaheim L. L., Sannes M., Egeland T. Expression of costimulatory molecule CD28 on T cells in human immunodeficiency virus type 1 infection: functional and clinical correlations. J Infect Dis. 1994 Apr;169(4):730–738. doi: 10.1093/infdis/169.4.730. [DOI] [PubMed] [Google Scholar]
  7. Caruso A., Cantalamessa A., Licenziati S., Peroni L., Prati E., Martinelli F., Canaris A. D., Folghera S., Gorla R., Balsari A. Expression of CD28 on CD8+ and CD4+ lymphocytes during HIV infection. Scand J Immunol. 1994 Nov;40(5):485–490. doi: 10.1111/j.1365-3083.1994.tb03494.x. [DOI] [PubMed] [Google Scholar]
  8. Choremi-Papadopoulou H., Viglis V., Gargalianos P., Kordossis T., Iniotaki-Theodoraki A., Kosmidis J. Downregulation of CD28 surface antigen on CD4+ and CD8+ T lymphocytes during HIV-1 infection. J Acquir Immune Defic Syndr. 1994 Mar;7(3):245–253. [PubMed] [Google Scholar]
  9. Croft M. Activation of naive, memory and effector T cells. Curr Opin Immunol. 1994 Jun;6(3):431–437. doi: 10.1016/0952-7915(94)90123-6. [DOI] [PubMed] [Google Scholar]
  10. Damle N. K., Mohagheghpour N., Hansen J. A., Engleman E. G. Alloantigen-specific cytotoxic and suppressor T lymphocytes are derived from phenotypically distinct precursors. J Immunol. 1983 Nov;131(5):2296–2300. [PubMed] [Google Scholar]
  11. Effros R. B., Boucher N., Porter V., Zhu X., Spaulding C., Walford R. L., Kronenberg M., Cohen D., Schächter 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. 1994 Nov-Dec;29(6):601–609. doi: 10.1016/0531-5565(94)90073-6. [DOI] [PubMed] [Google Scholar]
  12. Fagnoni F. F., Takamizawa M., Godfrey W. R., Rivas A., Azuma M., Okumura K., Engleman E. G. Role of B70/B7-2 in CD4+ T-cell immune responses induced by dendritic cells. Immunology. 1995 Jul;85(3):467–474. [PMC free article] [PubMed] [Google Scholar]
  13. Franceschi C., Monti D., Sansoni P., Cossarizza A. The immunology of exceptional individuals: the lesson of centenarians. Immunol Today. 1995 Jan;16(1):12–16. doi: 10.1016/0167-5699(95)80064-6. [DOI] [PubMed] [Google Scholar]
  14. Harlan D. M., Abe R., Lee K. P., June C. H. Potential roles of the B7 and CD28 receptor families in autoimmunity and immune evasion. Clin Immunol Immunopathol. 1995 May;75(2):99–111. doi: 10.1006/clin.1995.1058. [DOI] [PubMed] [Google Scholar]
  15. Hodes R. J. Molecular alterations in the aging immune system. J Exp Med. 1995 Jul 1;182(1):1–3. doi: 10.1084/jem.182.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Janeway C. A., Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994 Jan 28;76(2):275–285. doi: 10.1016/0092-8674(94)90335-2. [DOI] [PubMed] [Google Scholar]
  17. Jennings C., Rich K., Siegel J. N., Landay A. A phenotypic study of CD8+ lymphocyte subsets in infants using three-color flow cytometry. Clin Immunol Immunopathol. 1994 Apr;71(1):8–13. doi: 10.1006/clin.1994.1044. [DOI] [PubMed] [Google Scholar]
  18. June C. H., Ledbetter J. A., Linsley P. S., Thompson C. B. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 Jun;11(6):211–216. doi: 10.1016/0167-5699(90)90085-n. [DOI] [PubMed] [Google Scholar]
  19. June C. H., Vandenberghe P., Thompson C. B. The CD28 and CTLA-4 receptor family. Chem Immunol. 1994;59:62–90. [PubMed] [Google Scholar]
  20. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McFarland H. I., Nahill S. R., Maciaszek J. W., Welsh R. M. CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992 Aug 15;149(4):1326–1333. [PubMed] [Google Scholar]
  22. Phillips J. H., Lanier L. L. Lectin-dependent and anti-CD3 induced cytotoxicity are preferentially mediated by peripheral blood cytotoxic T lymphocytes expressing Leu-7 antigen. J Immunol. 1986 Mar 1;136(5):1579–1585. [PubMed] [Google Scholar]
  23. Posnett D. N., Sinha R., Kabak S., Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994 Feb 1;179(2):609–618. doi: 10.1084/jem.179.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Roederer M., Dubs J. G., Anderson M. T., Raju P. A., Herzenberg L. A., Herzenberg L. A. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest. 1995 May;95(5):2061–2066. doi: 10.1172/JCI117892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Roth M. D. Interleukin 2 induces the expression of CD45RO and the memory phenotype by CD45RA+ peripheral blood lymphocytes. J Exp Med. 1994 Mar 1;179(3):857–864. doi: 10.1084/jem.179.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rothstein D. M., Yamada A., Schlossman S. F., Morimoto C. Cyclic regulation of CD45 isoform expression in a long term human CD4+CD45RA+ T cell line. J Immunol. 1991 Feb 15;146(4):1175–1183. [PubMed] [Google Scholar]
  27. Rothstein G. Hematopoiesis in the aged: a model of hematopoietic dysregulation? Blood. 1993 Nov 1;82(9):2601–2604. [PubMed] [Google Scholar]
  28. Rowe J. W., Kahn R. L. Human aging: usual and successful. Science. 1987 Jul 10;237(4811):143–149. doi: 10.1126/science.3299702. [DOI] [PubMed] [Google Scholar]
  29. Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
  30. Sansoni P., Cossarizza A., Brianti V., Fagnoni F., Snelli G., Monti D., Marcato A., Passeri G., Ortolani C., Forti E. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood. 1993 Nov 1;82(9):2767–2773. [PubMed] [Google Scholar]
  31. Sansoni P., Silverman E. D., Khan M. M., Melmon K. L., Engleman E. G. Immunoregulatory T cells in man. Histamine-induced suppressor T cells are derived from a Leu 2+ (T8+) subpopulation distinct from that which gives rise to cytotoxic T cells. J Clin Invest. 1985 Feb;75(2):650–656. doi: 10.1172/JCI111743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Saukkonen J. J., Kornfeld H., Berman J. S. Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. J Acquir Immune Defic Syndr. 1993 Nov;6(11):1194–1204. [PubMed] [Google Scholar]
  33. Saxon A., Feldhaus J., Robins R. A. Single step separation of human T and B cells using AET treated srbc rosettes. J Immunol Methods. 1976;12(3-4):285–288. doi: 10.1016/0022-1759(76)90050-8. [DOI] [PubMed] [Google Scholar]
  34. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  35. Vingerhoets J. H., Vanham G. L., Kestens L. L., Penne G. G., Colebunders R. L., Vandenbruaene M. J., Goeman J., Gigase P. L., De Boer M., Ceuppens J. L. Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects. Clin Exp Immunol. 1995 Jun;100(3):425–433. doi: 10.1111/j.1365-2249.1995.tb03717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yamada H., Martin P. J., Bean M. A., Braun M. P., Beatty P. G., Sadamoto K., Hansen J. A. Monoclonal antibody 9.3 and anti-CD11 antibodies define reciprocal subsets of lymphocytes. Eur J Immunol. 1985 Dec;15(12):1164–1168. doi: 10.1002/eji.1830151204. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES