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.
-
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.
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).
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.
Metrics
-
- 2,567
- views
-
- 366
- downloads
-
- 34
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Immunology and Inflammation
The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
-
- Immunology and Inflammation
- Medicine
Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.
