ArticleJCI insight2022
Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 51 citations in OpenAlex.
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- Advances in natural killer cell immunotherapy for hematologic malignancies.Cancer biology & therapy · 2026Review
- Long-term depletion of KIR3DL01+ NK cells by adeno-associated viral-vectored antibody delivery alters chronic SIV infection.PLoS pathogens · 2026Article
- ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.bioRxiv : the preprint server for biology · 2026Article
- HLA-E single-chain trimer shields gene-edited allogeneic CAR T cells from NK cell attack.Blood advances · 2026Article
- Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy.Journal for immunotherapy of cancer · 2026Review
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- SMAD7 drives natural killer cell antitumor activity through canonical TGF-β blockade and non-canonical transcriptional activation of STAT5A.Journal for immunotherapy of cancer · 2026Article
- HLA-E as an Emerging Checkpoint and Biomarker in Personalized Cancer Immunotherapy.Current medical science · 2026Review
- Liver Transplantation Following Immune Checkpoint Inhibitor Therapy: What Do We Need to Know from Clinical and Immunological Perspective?International journal of molecular sciences · 2026Review
- Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes.Immunity · 2026Article
- Human pluripotent stem cell-derived innate and adaptive immune cells for cancer immunotherapy.Cell stem cell · 2026Review
- Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.Frontiers in cell and developmental biology · 2026Review
- SLy1-deficiency results in functional impaired, exhausted and senescent NK cells.Frontiers in immunology · 2026Article
- Single-cell transcriptomics and spatial validation reveal dysfunction of keratinocytes and NK cells driving acne development.Scientific reports · 2025Article
- Multidimensional plasticity of natural killer cells in tumours.Cell death & disease · 2025Review
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- Integrative and deep learning-based prediction of therapy response in ovarian cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa.Nature communications · 2025Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
NK cell exhaustion is caused by chronic exposure to activating stimuli during viral infection, tumorigenesis, and prolonged cytokine treatment. Evidence suggests that exhaustion may play a role in disease progression. However, relative to T cell exhaustion, the mechanisms underlying NK cell exhaustion and methods of reversing it are poorly understood. Here, we describe a potentially novel in vitro model of exhaustion that uses plate-bound agonists of the NK cell activating receptors NKp46 and NKG2D to induce canonical exhaustion phenotypes. In this model, prolonged activation resulted in downregulation of activating receptors, upregulation of checkpoint markers, decreased cytokine production and cytotoxicity in vitro, weakened glycolytic capacity, and decreased persistence, function, and tumor control in vivo. Furthermore, we discovered a beneficial effect of NK cell inhibitory receptor signaling during exhaustion. By simultaneously engaging the inhibitory receptor NKG2A during activation in our model, cytokine production and cytotoxicity defects were mitigated, suggesting that balancing positive and negative signals integrated by effector NK cells can be beneficial for antitumor immunity. Together, these data uncover some of the mechanisms underlying NK cell exhaustion in humans and establish our in vitro model as a valuable tool for studying the processes regulating exhaustion.
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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.