ArticleJCI insight2019
Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 92 citations in OpenAlex.
- Modulation of Mu-Opioid Receptor Expression and Functional Impairment of Natural Killer Cells in Neuropathic Pain: Implications for Biomarker Discovery and Personalized Therapies.Pharmaceuticals (Basel, Switzerland) · 2026Article
- 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
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- Phenotypes, mechanisms, and therapeutic strategies of natural killer cell immunosenescence.Immunity & ageing : I & A · 2025Review
- Aging and immunity: the age-old tango.Genes & development · 2025Review
- IRF4 expression by NK precursors predetermines exhaustion of NK cells during tumor metastasis.Nature immunology · 2025Article
- Chronic inflammation deters natural killer cell fitness and cytotoxicity in myeloid leukemia.Blood advances · 2025Article
- NKG2D triggering hampers DNAM-1-mediated signaling in human NK cells.Frontiers in immunology · 2025Article
- NK cell dysfunction in antiphospholipid syndrome.Frontiers in immunology · 2025Review
- Mechanisms of Cbl-Mediated Ubiquitination of Proteins in T and Natural Killer Cells and Effects on Immune Cell Functions.Life (Basel, Switzerland) · 2024Review
- Unlocking the therapeutic potential of the NKG2A-HLA-E immune checkpoint pathway in T cells and NK cells for cancer immunotherapy.Journal for immunotherapy of cancer · 2024Review
- Dysfunction of type 1 and type 2 immune cells: a lesson from exhausted-like ILC2s and their activation-induced cell death.International immunology · 2024Review
- Tumor-induced natural killer cell dysfunction is a rapid and reversible process uncoupled from the expression of immune checkpoints.Science advances · 2024Article
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- Suppressive effects of obesity on NK cells: is it time to incorporate obesity as a clinical variable for NK cell-based cancer immunotherapy regimens?Journal for immunotherapy of cancer · 2024Article
- The role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia.Cell communication and signaling : CCS · 2024Review
- Outsmarting trogocytosis to boost CAR NK/T cell therapy.Molecular cancer · 2023Review
- Intratumoral co-injection of NK cells and NKG2A-neutralizing monoclonal antibodies.EMBO molecular medicine · 2023Article
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE characterized by up-regulation of the terminal differentiation marker KLRG1 and by down-regulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimized NCE compared to control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulations on NK cells has been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation there is an increase of MULT1, and NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, by sustaining NKG2D expression and by preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased anti-tumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell-based immunotherapy.
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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.