Skewed maturation of memory HIV-specific CD8 T lymphocytes (original) (raw)

Nature volume 410, pages 106–111 (2001)Cite this article

Abstract

Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities1,2,3 and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8+ T-cell populations, identified four subsets of HIV- and CMV-specific CD8+ T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA+CCR7+ → CD45RA-CCR7+ → CD45RACD45RA-CCR7- → CD45RA+CCR7-. Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7+CD8+ T-cell subsets) that the differentiation of antigen-specific CD8+ T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7+CD8+ cell subsets, followed by a phase of functional maturation encompassing the CCR7-CD8+ cell subsets. The distribution of these populations in HIV- and CMV-specific CD8+ T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA-CCR7- cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA+CCR7- cells. These results demonstrate a skewed maturation of HIV-specific memory CD8+ T cells during HIV infection.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Butcher, E. C. & Picker, L. J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).
    Article ADS CAS PubMed Google Scholar
  2. Sallusto, F. et al. The role of chemokine receptors in primary, effector, and memory immune responses. Annu. Rev. Immunol. 18, 593–620 (2000).
    Article CAS PubMed Google Scholar
  3. Sallusto, F. et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
    Article ADS CAS PubMed Google Scholar
  4. Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370, 463–467 (1994).
    Article ADS CAS PubMed Google Scholar
  5. Schmitz, J. E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).
    Article ADS CAS PubMed Google Scholar
  6. Appay, V. et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).
    Article CAS PubMed PubMed Central Google Scholar
  7. Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
    Article ADS CAS PubMed Google Scholar
  8. Ogg, G. S. et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).
    Article ADS CAS PubMed Google Scholar
  9. Johnson, R. P. et al. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. J. Immunol. 147, 1512–1521 (1991).
    CAS PubMed Google Scholar
  10. Michie, C. A. et al. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).
    Article ADS CAS PubMed Google Scholar
  11. Callan, M. F. C. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr Virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).
    Article CAS PubMed PubMed Central Google Scholar
  12. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).
    Article CAS PubMed PubMed Central Google Scholar
  13. Lyons, A. B. & Parish, C. R. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods 171, 131–137 (1994).
    Article CAS PubMed Google Scholar
  14. Gerdes, J. et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J. Immunol. 133, 1710–1715 (1984).
    CAS PubMed Google Scholar
  15. Pantaleo, G. et al. Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+CD25- T cell population. J. Immunol. 144, 1696–1704 (1990).
    CAS PubMed Google Scholar
  16. Pantaleo, G. et al. CD8+ T lymphocytes of patients with AIDS maintain normal broad cytolytic function despite the loss of human immunodeficiency virus-specific cytotoxicity. Proc. Natl Acad. Sci. USA 87, 4818–4822 (1990).
    Article ADS CAS PubMed PubMed Central Google Scholar
  17. Sallusto, F. et al. Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur. J. Immunol. 29, 2037–2045 (1999).
    Article CAS PubMed Google Scholar
  18. Wills, M. R. et al. 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, 7569–7579 (1996).
    CAS PubMed PubMed Central Google Scholar
  19. Fleury, S. et al. Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy. Nature Medicine 4, 794–801 (1998).
    Article CAS PubMed Google Scholar
  20. Fleury, S. et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 97, 5393–5398 (2000).
    Article ADS CAS PubMed PubMed Central Google Scholar
  21. Andersson, J. et al. Perforin is not co-expressed with Granzyme A within cytoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. AIDS 13, 1295–1303 (1998).
    Article Google Scholar
  22. Wolthers, K. C. et al. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 274, 1543–1547 (1996).
    Article ADS CAS PubMed Google Scholar
  23. Mitchison, N. A. et al. Proc. R. Soc. Lond. 161, 275–293 (1964).
    Article ADS CAS PubMed Google Scholar
  24. Zinkernagel, R. M. Immunology taught by viruses. Science 271, 173–178 (1996).
    Article ADS CAS PubMed Google Scholar
  25. Rosenberg, E. S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).
    Article ADS CAS PubMed Google Scholar
  26. Miedema, F. et al. Changing virus-host interactions in the course of HIV-1 infection. Immunol. Rev. 140, 35–72 (1994).
    Article CAS PubMed Google Scholar

Download references

Acknowledgements

We thank A. Wilson for providing the Extravidin-Cy5 conjugate. This work was supported by an SNF grant (Tandem project), by the EuroVae project (G.P.) and by the Leenards Foundation (G.P.), and by an NIH grant (Acute Infection, G.P.; R.P.S.). P.C. is supported by a Doctoral Award of the Medical Research Council of Canada. R.P.S. is a Canadian Institutes of Health Research senior scientist.

Author information

Author notes

  1. Patrick Champagne and Graham S. Ogg: These authors contributed equally to this work

Authors and Affiliations

  1. Divisions of Immunology and Allergy and Infectious Diseases, Department of Medicine, Laboratory of AIDS Immunopathogenesis, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, 1011, Switzerland
    Patrick Champagne, Christian Knabenhans, Kim Ellefsen, Massimo Nobile, G. Paolo Rizzardi, Sylvain Fleury & Giuseppe Pantaleo
  2. Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, H2W 1T8
    Patrick Champagne & Rafick-P. Sékaly
  3. Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, H3A 2T5, Canada
    Patrick Champagne & Rafick-P. Sékaly
  4. MRC Human Immunology Unit, Institute for Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK
    Graham S. Ogg, Abigail S. King, Victor Appay, Sarah Rowland-Jones & Andrew J. McMichael
  5. Molecular Tumor genetics and Immunogenetics, Max-Delrbrück-Center for Molecular Medicine, Berlin, 13092, Germany
    Martin Lipp & Reinhold Förster
  6. Department of Microbiology and Immunology, McGill University, Montréal, H3A 2T5
    Rafick-P. Sékaly
  7. Département de Microbiologie et Immunologie, Université de Montréal, Montréal, H2W 1T8, Canada
    Rafick-P. Sékaly

Authors

  1. Patrick Champagne
    You can also search for this author inPubMed Google Scholar
  2. Graham S. Ogg
    You can also search for this author inPubMed Google Scholar
  3. Abigail S. King
    You can also search for this author inPubMed Google Scholar
  4. Christian Knabenhans
    You can also search for this author inPubMed Google Scholar
  5. Kim Ellefsen
    You can also search for this author inPubMed Google Scholar
  6. Massimo Nobile
    You can also search for this author inPubMed Google Scholar
  7. Victor Appay
    You can also search for this author inPubMed Google Scholar
  8. G. Paolo Rizzardi
    You can also search for this author inPubMed Google Scholar
  9. Sylvain Fleury
    You can also search for this author inPubMed Google Scholar
  10. Martin Lipp
    You can also search for this author inPubMed Google Scholar
  11. Reinhold Förster
    You can also search for this author inPubMed Google Scholar
  12. Sarah Rowland-Jones
    You can also search for this author inPubMed Google Scholar
  13. Rafick-P. Sékaly
    You can also search for this author inPubMed Google Scholar
  14. Andrew J. McMichael
    You can also search for this author inPubMed Google Scholar
  15. Giuseppe Pantaleo
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toGiuseppe Pantaleo.

Rights and permissions

About this article

Cite this article

Champagne, P., Ogg, G., King, A. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes.Nature 410, 106–111 (2001). https://doi.org/10.1038/35065118

Download citation