Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

Nature Medicine volume 6, pages 1036–1042 (2000)Cite this article

Abstract

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Correlation between TRECs and naive T-cell numbers.
Figure 2: The model behavior as a function of age (a, b and c).
Figure 3: The model behavior of an HIV-1 infected, 30-year old individual over a time period of one year.
Figure 4: In vivo dilution of TRECs.
Figure 5: Effect of HAART on TREC content.

Similar content being viewed by others

References

  1. Gaulton, G.N., Scobie, J.V. & Rosenzweig, M. HIV-1 and the thymus. AIDS. 11, 403–414 (1997).

    Article  CAS  Google Scholar 

  2. Hazenberg, M.D., Clark, D.R. & Miedema, F. Tilted balance of T cell renewal in HIV-1 infection. AIDS Rev. 1, 67–73 (1999).

    Google Scholar 

  3. Douek, D.C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1999).

    Article  Google Scholar 

  4. Livak, F. & Schatz, D.G. T-cell receptor alpha locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol. Cell. Biol. 16, 609–618 (1998).

    Article  Google Scholar 

  5. De Villartay, J.P., Hockett, R.D., Coran, D., Korsmeyer, S.J. & Cohen, D.I. Deletion of the human T-cell receptor δ-gene by a site specific recombination. Nature 335, 170–174 (1988).

    Article  CAS  Google Scholar 

  6. Breit, T.M. et al. Rearrangements of the human TCRD-deleting elements. Immunogenetics 40, 70–75 (1994).

    Article  CAS  Google Scholar 

  7. Verschuren, M.C.M. et al. Preferential rearrangements of the T cell receptor—-deleting elements in human T cells. J. Immunol. 158, 1208–1216 (1997).

    CAS  PubMed  Google Scholar 

  8. Breit, T.M., Verschuren, M.C.M., Wolvers-Tettero, I.L.M, Van Gastel-Mol, E.J. & Van Dongen, J.J.M. Human T cell leukemias with continuous V(D)J recombinase activity for TCR-δ gene deletion. J. Immunol. 159, 4341–4349 (1997).

    CAS  PubMed  Google Scholar 

  9. Nakajima, P.B., Menetski, J.P., Roth, D.B., Gellert, M. & Bosma, M.J. V-D-J- Rearrangements at the T cell receptor δ locus in mouse thymocytes of the αβ lineage. Immunity 3, 609–621 (1995).

    Article  CAS  Google Scholar 

  10. Zhang, L. et al. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J. Exp. Med. 190, 725–732 (1999).

    Article  CAS  Google Scholar 

  11. Jamieson, B.D. et al. Generation of functional thymocytes in the human adult. Immunity 10, 569–575 (1999).

    Article  CAS  Google Scholar 

  12. Poulin, J.-F. et al. Direct evidence for thymic function in adult humans. J. Exp. Med. 190, 479–486 (1999).

    Article  CAS  Google Scholar 

  13. Hatzakis, A. et al. Effect of recent thymic emigrants on progression of HIV-1 disease. Lancet 355, 599–604 (2000).

    Article  CAS  Google Scholar 

  14. Hazenberg, M.D. et al. T cell division in human immunodeficiency virus (HIV-1)-infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active anti-retroviral therapy. Blood 95, 249–255 (2000).

    CAS  PubMed  Google Scholar 

  15. Meyaard, L., Otto, S.A., Keet, I.P.M., Roos, M.Th.L. & Miedema, F. Programmed death of T cells in HIV-1 infection: no correlation with progression to disease. J. Clin. Invest. 93, 982–988 (1994).

    Article  CAS  Google Scholar 

  16. Grossman, Z., Herberman, R.B. & Dimitrov, D.S. T cell turnover in SIV infection. Science 284, 555a–1999).

  17. 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 

  18. Kong, F.-K. Chen, C.-L.H., Six, A., Hockett, R.D. & Cooper, M.D. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl. Acad. Sci. USA 96, 1536–1540 (1999).

    Article  CAS  Google Scholar 

  19. Sprent, J. Lifespan of naive, memory and effector lymphocytes. Curr. Op. Immunol. 5, 433–438 (1993).

    Article  CAS  Google Scholar 

  20. Mclean, A.R. & Michie, C.A. In vivo estimates of division and death rates of human T lymphocytes. Proc. Natl. Acad. Sci. USA 92, 3707–3711 (1995).

    Article  CAS  Google Scholar 

  21. Walker, R.E. et al. Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration in HIV-infected adults. Nature Med. 4, 852–856 (1998).

    Article  CAS  Google Scholar 

  22. Messele, T. et al. Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts. J. Clin. Exp. Immunol. 115, 443–450 (1999).

    Article  CAS  Google Scholar 

  23. Sachsenberg, N. et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J. Exp. Med. 187, 1295–1303 (1998).

    Article  CAS  Google Scholar 

  24. Roos, M.Th.L. et al. Viro-immunological studies in acute HIV-1 infection. AIDS 8, 1533–1538 (1994).

    Article  CAS  Google Scholar 

  25. Roos, M.Th.L. et al. Viral phenotype and immune response in primary human immunodeficiency virus type 1 (HIV-1) infection. J. Infect. Dis. 165, 427–432 (1992).

    Article  CAS  Google Scholar 

  26. HIntzen, R.Q. et al. Regulation of CD27 expression on subsets of mature T lymphocytes. J. Immunol. 151, 2426–2435 (1993).

    CAS  PubMed  Google Scholar 

  27. Tough, D.F. & Sprent, J. Turnover of naive- and memory-phenotype T cells. J. Exp. Med. 179, 1127–1135 (1994).

    Article  CAS  Google Scholar 

  28. Unutmaz, D., Baldoni, F. & Abrignani, S. Human naive T cells activated by cytokines differentiate into a split phenotype with functional features intermediate between naive and memory cells. Int. Immunol. 7, 1417–1424 (1995).

    Article  CAS  Google Scholar 

  29. Unutmaz, D., Pileri, P. & Abrignani, S. Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J. Exp. Med. 180, 1159–1164 (1994).

    Article  CAS  Google Scholar 

  30. 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  CAS  Google Scholar 

  31. Wolthers, K.C., Noest, A.J., Otto, S.A., Miedema, F. & DeBoer, R.J. Normal telomere lengths in naive and memory CD4+ T cells in HIV-1 infection: a mathematical interpretation. AIDS Res. Hum. Retroviruses. 15, 1053–1062 (1999).

    Article  CAS  Google Scholar 

  32. Clark, D.R., De Boer, R.J., Wolthers, K.C. & Miedema, F. T cell dynamics in HIV-1 infection. Adv. Immunol. 73, 301–327 (1999).

    Article  CAS  Google Scholar 

  33. Pakker, N.G. et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nature Med. 4, 208–214 (1998).

    Article  CAS  Google Scholar 

  34. Hellerstein, M.K. & McCune, J.M. T cell turnover in HIV-1 disease. Immunity. 7, 583–589 (1997).

    Article  CAS  Google Scholar 

  35. George, A.J.T. & Ritter, M.A. Thymic involution with aging: obsolescence or good housekeeping? Immunol. Today 17, 267–272 (1996).

    Article  CAS  Google Scholar 

  36. Boom van Noorloos, A.A., Van Beek, A.A.M. & Melief, C.J.M. Cryopreservation of cells for immunological typing of non-Hodgkin's lymphomas. Cancer Res. 40, 2890–2894 (1980).

    Google Scholar 

  37. 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  Google Scholar 

  38. Baars, P.A., Maurice, M.M., Rep, M., Hooibrink, B. & Van Lier, R.A.W. Heterogeneity of the circulating human CD4+ T-cell population: Further evidence that the CD4+CD45RA−CD27− T-cell subset contains specialized primed cells. J. Immunol. 154, 17–25 (1995).

    CAS  PubMed  Google Scholar 

  39. Hellerstein, M. et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans. Nature Med. 5, 83–89 (1999).

    Article  CAS  Google Scholar 

  40. Pongers-Willemse, M.J. et al. Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes. Leukemia 12, 2006–2014 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Patients and physicians are gratefully acknowledged for their participation in the studies. We thank Marja J. Willemse and Bas Dutilh for technical assistance, and Hanneke Schuitemaker and Rene van Lier for critical reading of the manuscript. This study was financially supported by the Dutch AIDS Foundation, the Netherlands Ministry of Foreign Affairs and the Ethiopian Ministry of Health (EHNRI-ENARP), Hoffman-La Roche, Bristol Myers Squibb and Dutch Cancer Society / Koningin Wilhelmina Fonds (grant EUR 95-1015; M.V. and J.vD.).

Author information

Authors and Affiliations

  1. Department of Clinical Viro-Immunology, CLB, and the Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066CX, Amsterdam, The Netherlands

    Mette D. Hazenberg, Sigrid A. Otto, Dörte Hamann & Frank Miedema

  2. Department of Internal Medicine, University Medical Center, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    James W.T. Cohen Stuart & Jan C.C. Borleffs

  3. Department of Virology, Eijkman-Winkler Institute, University Medical Center, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    James W.T. Cohen Stuart & Charles A.B. Boucher

  4. Department of Immunology, Erasmus University, P.O. Box 1738, Rotterdam, 3000 DR, The Netherlands

    Martie C.M. Verschuren & Jacques J.M. van Dongen

  5. Department of Public Health and Environment, Municipal Health Service, P.O. Box 2200, Amsterdam, 1000 CE, The Netherlands

    Roel A. Coutinho

  6. Division of Infectious Diseases, Department of Internal Medicine, Tropical medicine and AIDS and the National AIDS Therapy Evaluation Center (NATEC), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, The Netherlands

    Joep M.A. Lange

  7. Ethiopian-Netherlands AIDS Research Project (ENARP) at the Ethiopian Health and Nutrition Research Institute (EHNRI), P.O. Box 1242, Addis Ababa, Ethiopia

    Tobias F. Rinke de Wit & Aster Tsegaye

  8. Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH, The Netherlands

    Rob J. de Boer

  9. Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Frank Miedema

Authors
  1. Mette D. Hazenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sigrid A. Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James W.T. Cohen Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martie C.M. Verschuren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan C.C. Borleffs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles A.B. Boucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roel A. Coutinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joep M.A. Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tobias F. Rinke de Wit
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aster Tsegaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jacques J.M. van Dongen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dörte Hamann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Rob J. de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Frank Miedema
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Miedema.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hazenberg, M., Otto, S., Stuart, J. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med 6, 1036–1042 (2000). https://doi.org/10.1038/79549

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79549

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing