1. Immunology and Inflammation
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Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients

  1. Cécile Alanio
  2. Francesco Nicoli
  3. Philippe Sultanik
  4. Tobias Flecken
  5. Brieuc Perot
  6. Darragh Duffy
  7. Elisabetta Bianchi
  8. Annick Lim
  9. Emmanuel Clave
  10. Marit M van Buuren
  11. Aurélie Schnuriger
  12. Kerstin Johnsson
  13. Jeremy Boussier
  14. Antoine Garbarg-Chenon
  15. Laurence Bousquet
  16. Estelle Mottez
  17. Ton N Schumacher
  18. Antoine Toubert
  19. Victor Appay
  20. Farhad Heshmati
  21. Robert Thimme
  22. Stanislas Pol
  23. Vincent Mallet
  24. Matthew L Albert  Is a corresponding author
  1. Institut Pasteur, France
  2. University Pierre et Marie Curie, France
  3. Albert-Ludwigs-Universität, Germany
  4. Assistance publique - hôpitaux de Paris, France
  5. The Netherlands Cancer Institute, Netherlands
  6. Lunds University, Sweden
  7. Assistance publique - Hôpitaux de Paris, France
  8. Université Paris Descartes, France
  9. Assistance Publique - Hôpitaux de Paris, France
  10. Albert-Ludwigs-Universität Freiburg, Germany
Research Article
  • Cited 29
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Cite this article as: eLife 2015;4:e07916 doi: 10.7554/eLife.07916

Abstract

Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8+ T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8+ T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8+ T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.

Article and author information

Author details

  1. Cécile Alanio

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Francesco Nicoli

    Centre d'Immunologie et des Maladies Infectieuses, University Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Philippe Sultanik

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Tobias Flecken

    The University Medical Center Freiburg, Department of Internal Medicine II, Albert-Ludwigs-Universität, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Brieuc Perot

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Darragh Duffy

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Elisabetta Bianchi

    Immunoregulation Unit, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Annick Lim

    Plateforme d'Immunoscope, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Emmanuel Clave

    Hôpital Saint Louis, Assistance publique - hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Marit M van Buuren

    Department of Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Aurélie Schnuriger

    Laboratoire de virologie, Hôpital Armand-Trousseau, Assistance publique - hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Kerstin Johnsson

    Mathematics, Faculty of Engineering, Lunds University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  13. Jeremy Boussier

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Antoine Garbarg-Chenon

    Laboratoire de virologie, Hôpital Armand-Trousseau, Assistance publique - Hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Laurence Bousquet

    Institut Cochin, Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Estelle Mottez

    Centre d'Immunologie Humaine, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Ton N Schumacher

    Department of Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  18. Antoine Toubert

    Hôpital Saint-Louis, Assistance publique - hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Victor Appay

    Centre d'Immunologie et des Maladies Infectieuses, University Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  20. Farhad Heshmati

    Etablissement Français du Sang, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  21. Robert Thimme

    The University Medical Center Freiburg, Department of Internal Medicine II, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  22. Stanislas Pol

    Institut Cochin, Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  23. Vincent Mallet

    Institut Cochin, Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  24. Matthew L Albert

    Unités de Recherche Internationales Mixtes Pasteur, Institut Pasteur, Paris, France
    For correspondence
    albertm@pasteur.fr
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: 29 cHCV, 37 SVR, and 18 cHBV patients were included (Table 1). All subjects were followed in the Liver Unit of H�pital Cochin (Paris, France) or the Department of Internal Medicine II (Freiburg, Germany). French samples were obtained as part of study protocol C11-33 approved by the INSERM clinical investigation department with ethical approval from the CPP Ile-de-France II, Paris (ClinicalTrials.gov identifier: n{degree sign}NCT01534728). German samples were obtained in the University Hospital Freiburg according to regulations of local ethic committee. Both study protocols conformed to the ethical guidelines of the Declaration of Helsinki, and patients provided informed consent.

Reviewing Editor

  1. Rafi Ahmed, Emory, United States

Publication history

  1. Received: April 3, 2015
  2. Accepted: November 12, 2015
  3. Accepted Manuscript published: November 14, 2015 (version 1)
  4. Version of Record published: January 19, 2016 (version 2)

Copyright

© 2015, Alanio et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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