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
-
- 2,553
- views
-
- 365
- 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
As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
-
- Immunology and Inflammation
Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.
