Peripheral Natural Killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion
- Inserm, France
- International Center for Infectiology Research (CIRI), France
- CHU Limoges, France
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.
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RNAseqNCBI Gene Expression Omnibus, GSE153946.
Article and author information
Author details
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.
Reviewing Editor
- Stipan Jonjic, University of Rijeka, Croatia
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).
Version history
- Received: June 16, 2020
- Accepted: January 28, 2021
- Accepted Manuscript published: January 28, 2021 (version 1)
- 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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Peripheral Natural Killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion
eLife 10:e60095.
https://doi.org/10.7554/eLife.60095
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