1. Immunology and Inflammation
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Peripheral Natural Killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Research Article
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Cite this article as: eLife 2021;10:e60095 doi: 10.7554/eLife.60095

Abstract

Antiviral effectors such as Natural Killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterized. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE153946.

The following data sets were generated

Article and author information

Author details

  1. Marie Marotel

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Marine Villard

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Annabelle Drouillard

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Issam Tout

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Laurie Besson

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Omran Allatif

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Marine Pujol

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Yamila Rocca

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Michelle Ainouze

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Guillaume Roblot

    Immunology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Sébastien Viel

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5085-443X
  12. Melissa Gomez

    Hepathology, CHU Limoges, Limoges, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Veronique Loustaud

    Hepathology, CHU Limoges, Limoges, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Sophie Alain

    Hepathology, CHU Limoges, Limoges, France
    Competing interests
    The authors declare that no competing interests exist.
  15. David Durantel

    Cancerology, Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Thierry Walzer

    International Center for Infectiology Research (CIRI), Lyon, France
    For correspondence
    thierry.walzer@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0857-8179
  17. Uzma Hasan

    Immunology, Inserm, Lyon, France
    For correspondence
    uzma.hasan@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
  18. Antoine Marçais

    International Center for Infectiology Research (CIRI), Lyon, France
    For correspondence
    antoine.marcais@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3591-6268

Funding

Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ22398)

  • Uzma Hasan

Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ11169)

  • Uzma Hasan

Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ19856)

  • Uzma Hasan

Agence Nationale de la Recherche (BaNK)

  • Antoine Marçais

Agence Nationale de la Recherche (SPHINKS)

  • Thierry Walzer

Association de Recherche sur le Cancer (Equipe labellisée)

  • Thierry Walzer

H2020 European Research Council (ERC-Stg 281025)

  • Thierry Walzer

La Ligue Nationale contre le Cancer (Graduate student fellowship)

  • Marie Marotel

La Ligue du Rhone (LNCC)

  • Uzma Hasan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All participants provided written informed consent in accordance with the procedure approved by the local ethics committee (Comité de Protection des Personnes, Centre Hospitalier Universitaire de Limoges, Limoges, France) and the Interventional research protocol involving human samples (Code promotor LiNKeB project: 87RI18-0021).

Reviewing Editor

  1. Stipan Jonjic, University of Rijeka, Croatia

Publication history

  1. Received: June 16, 2020
  2. Accepted: January 28, 2021
  3. Accepted Manuscript published: January 28, 2021 (version 1)
  4. Version of Record published: February 8, 2021 (version 2)

Copyright

© 2021, Marotel 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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