Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Jun 1;169(6):1993–2005. doi: 10.1084/jem.169.6.1993

T cell memory. Long-term persistence of virus-specific cytotoxic T cells

PMCID: PMC2189353  PMID: 2471771

Abstract

This study documents that virus-specific CTL can persist indefinitely in vivo. This was accomplished by transferring Thy-1.1 T cells into Thy- 1.2 recipient mice to specifically identify the donor T cell population and to characterize its antigenic specificity and function by using a virus-specific CTL assay. Thy-1.1+ T cells from mice previously immunized with lymphocytic choriomeningitis virus (LCMV) were transferred into Thy-1.2 mice persistently infected with LCMV. The transferred LCMV-specific CTL (Thy-1.1+ CD8+) eliminate virus from the chronically infected carriers and persist in the recipient mice in small numbers, comprising only a minor fraction of the total T cells. Upon re-exposure to virus, these long-lived "resting" CD8+ T cells proliferate in vivo to become the predominant cell population. These donor CD8+ T cells can be recovered up to a year post-transfer and still retain antigenic specificity and biological function. They kill LCMV infected H-2-matched cells in vitro and can eliminate virus upon transfer into a second infected host. In addition, these long-lived CD8+ T cells appear not to be dependent on help from CD4+ T cells, since depletion of CD4+ T cells has minimal or no effect on their biological properties (proliferation, CTL response, viral clearance). These donor CTL also exhibit an immunodominance over the host-derived LCMV-specific CTL response. When both host and donor T cells are present, the donor CTL response is dominant over the potential CTL response of the cured carrier host. Taken together, these results suggest that virus-specific CTL can persist for the life span of the host as memory cells.

Full Text

The Full Text of this article is available as a PDF (887.0 KB).

Selected References

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

  1. Ahmed R., Butler L. D., Bhatti L. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J Virol. 1988 Jun;62(6):2102–2106. doi: 10.1128/jvi.62.6.2102-2106.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmed R., Jamieson B. D., Porter D. D. Immune therapy of a persistent and disseminated viral infection. J Virol. 1987 Dec;61(12):3920–3929. doi: 10.1128/jvi.61.12.3920-3929.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ahmed R., King C. C., Oldstone M. B. Virus-lymphocyte interaction: T cells of the helper subset are infected with lymphocytic choriomeningitis virus during persistent infection in vivo. J Virol. 1987 May;61(5):1571–1576. doi: 10.1128/jvi.61.5.1571-1576.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ahmed R., Salmi A., Butler L. D., Chiller J. M., Oldstone M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984 Aug 1;160(2):521–540. doi: 10.1084/jem.160.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bastin J., Rothbard J., Davey J., Jones I., Townsend A. Use of synthetic peptides of influenza nucleoprotein to define epitopes recognized by class I-restricted cytotoxic T lymphocytes. J Exp Med. 1987 Jun 1;165(6):1508–1523. doi: 10.1084/jem.165.6.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cannon M. J., Stott E. J., Taylor G., Askonas B. A. Clearance of persistent respiratory syncytial virus infections in immunodeficient mice following transfer of primed T cells. Immunology. 1987 Sep;62(1):133–138. [PMC free article] [PubMed] [Google Scholar]
  8. Cheever M. A., Thompson D. B., Klarnet J. P., Greenberg P. D. Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells. J Exp Med. 1986 May 1;163(5):1100–1112. doi: 10.1084/jem.163.5.1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  10. Finberg R., Benacerraf B. Induction, control and consequences of virus specific cytotoxic T cells. Immunol Rev. 1981;58:157–180. doi: 10.1111/j.1600-065x.1981.tb00353.x. [DOI] [PubMed] [Google Scholar]
  11. Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. 1987 Apr 30-May 6Nature. 326(6116):881–882. doi: 10.1038/326881a0. [DOI] [PubMed] [Google Scholar]
  12. Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984 Dec 1;160(6):1717–1735. doi: 10.1084/jem.160.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jamieson B. D., Ahmed R. T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2265–2268. doi: 10.1073/pnas.85.7.2265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jamieson B. D., Butler L. D., Ahmed R. Effective clearance of a persistent viral infection requires cooperation between virus-specific Lyt2+ T cells and nonspecific bone marrow-derived cells. J Virol. 1987 Dec;61(12):3930–3937. doi: 10.1128/jvi.61.12.3930-3937.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kasaian M. T., Biron C. A. The activation of IL-2 transcription in L3T4+ and Lyt-2+ lymphocytes during virus infection in vivo. J Immunol. 1989 Feb 15;142(4):1287–1292. [PubMed] [Google Scholar]
  16. Lukacher A. E., Braciale V. L., Braciale T. J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med. 1984 Sep 1;160(3):814–826. doi: 10.1084/jem.160.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mizuochi T., Golding H., Rosenberg A. S., Glimcher L. H., Malek T. R., Singer A. Both L3T4+ and Lyt-2+ helper T cells initiate cytotoxic T lymphocyte responses against allogenic major histocompatibility antigens but not against trinitrophenyl-modified self. J Exp Med. 1985 Aug 1;162(2):427–443. doi: 10.1084/jem.162.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mizuochi T., Hügin A. W., Morse H. C., 3rd, Singer A., Buller R. M. Role of lymphokine-secreting CD8+ T cells in cytotoxic T lymphocyte responses against vaccinia virus. J Immunol. 1989 Jan 1;142(1):270–273. [PubMed] [Google Scholar]
  19. Morrison L. A., Lukacher A. E., Braciale V. L., Fan D. P., Braciale T. J. Differences in antigen presentation to MHC class I-and class II-restricted influenza virus-specific cytolytic T lymphocyte clones. J Exp Med. 1986 Apr 1;163(4):903–921. doi: 10.1084/jem.163.4.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nabholz M., MacDonald H. R. Cytolytic T lymphocytes. Annu Rev Immunol. 1983;1:273–306. doi: 10.1146/annurev.iy.01.040183.001421. [DOI] [PubMed] [Google Scholar]
  21. Oldstone M. B., Blount P., Southern P. J., Lampert P. W. Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature. 1986 May 15;321(6067):239–243. doi: 10.1038/321239a0. [DOI] [PubMed] [Google Scholar]
  22. Oldstone M. B., Whitton J. L., Lewicki H., Tishon A. Fine dissection of a nine amino acid glycoprotein epitope, a major determinant recognized by lymphocytic choriomeningitis virus-specific class I-restricted H-2Db cytotoxic T lymphocytes. J Exp Med. 1988 Aug 1;168(2):559–570. doi: 10.1084/jem.168.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reddehase M. J., Mutter W., Münch K., Bühring H. J., Koszinowski U. H. CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol. 1987 Oct;61(10):3102–3108. doi: 10.1128/jvi.61.10.3102-3108.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sethi K. K., Omata Y., Schneweis K. E. Protection of mice from fatal herpes simplex virus type 1 infection by adoptive transfer of cloned virus-specific and H-2-restricted cytotoxic T lymphocytes. J Gen Virol. 1983 Feb;64(Pt 2):443–447. doi: 10.1099/0022-1317-64-2-443. [DOI] [PubMed] [Google Scholar]
  25. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  26. VOLKERT M. STUDIES ON IMMUNOLOGICAL TOLERANCE TO LCM VIRUS. 2. TREATMENT OF VIRUS CARRIER MICE BY ADOPTIVE IMMUNIZATION. Acta Pathol Microbiol Scand. 1963;57:465–487. [PubMed] [Google Scholar]
  27. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
  28. Zinkernagel R. M., Welsh R. M. H-2 compatibility requirement for virus-specific T cell-mediated effector functions in vivo. I. Specificity of T cells conferring antiviral protection against lymphocytic choriomeningitis virus is associated with H-2K and H-2D. J Immunol. 1976 Nov;117(5 Pt 1):1495–1502. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES