ArticleThe Journal of clinical investigation2019
Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
119 citing papers in PubMed, 168 citations in OpenAlex.
- Restoration of HBV-specific CD8Signal transduction and targeted therapy · 2021Trial
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- Next-generation natural killer cell therapy: bench to bedside and beyond.Signal transduction and targeted therapy · 2026Review
- The Cardio-Onco-Immune Axis: immunopathological mechanisms in the cardiac microenvironment of checkpoint inhibitor-induced myocarditis.Acta pharmacologica Sinica · 2026Review
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- Epigenetic activation of NK-cell effector programs and caspase-8-dependent apoptosis mediates the antitumor activity of LGP in NSCLC.Journal of ginseng research · 2026Article
- Immune Circuit Rewiring by HDAC Inhibition Enables Response to Dual Checkpoint Blockade in Metastatic Breast Cancer.Cancer research · 2026Article
- ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.bioRxiv : the preprint server for biology · 2026Article
- Review
- Defining the role of natural killer cells in acute myeloid leukemia through the lens of single-cell omics.Frontiers in immunology · 2026Review
- Scalable production process development for NK cells targeting large-scale expansion.Regenerative therapy · 2025Article
- From tumor immunotherapy to myocardial injury: A mechanistic discussion of immune checkpoint inhibitor‑related myocarditis (Review).Molecular medicine reports · 2025Review
- Leveraging the heterogeneity of the NK cell repertoire for the development of immunotherapies for acute leukemia.Journal of translational medicine · 2025Review
- Molecular Interactions Between NK Cells and Acute Leukemic Cells: KIR2DL5 Drastically Limits NK Cell Responses.Journal of clinical immunology · 2025Article
- Cancer systems immunology reveals myeloid-T cell interactions and B cell activation mediate response to checkpoint inhibition in metastatic breast cancer.bioRxiv : the preprint server for biology · 2025Article
- Article
- Immune profiling of kidney transplant recipients: the role of Tribbles-1, Perforin, and Granzyme B in chronic humoral rejection.Molecular biology reports · 2025Article
- Epigenetic regulators combined with tumour immunotherapy: current status and perspectives.Clinical epigenetics · 2025Review
- Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.Nature reviews. Drug discovery · 2025Review
59 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
A population of Natural Killer (NK) cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human cytomegalovirus (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon re-stimulation, persistence, and epigenetic remodeling of the IFNG locus. Chronic antigen stimulation drives CD8+ memory T cell proliferation while also inducing genome-wide epigenetic reprograming and dysfunction. We hypothesized that chronic stimulation could similarly induce epigenetic reprograming and dysfunction in NK cells. Here we show that chronic stimulation of adaptive NK cells through NKG2C using plate-bound agonistic antibodies in combination with IL-15 drove robust proliferation and activation of CD3-CD56dimCD57+NKG2C+ NK cells while simultaneously inducing high expression of the checkpoint inhibitory receptors LAG-3 and PD-1. Marked induction of checkpoint inhibitory receptors was also observed on the surface of adaptive NK cells co-cultured with HCMV-infected endothelial cells. Chronically stimulated adaptive NK cells were dysfunctional when challenged with tumor targets. These cells exhibited a pattern of epigenetic reprograming, with genome-wide alterations in DNA methylation. Our study has important implications for cancer immunotherapy and suggest that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.