NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development
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The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1-/-) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1-/- mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.
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NKG2D is constitutively expressed on many immune cells, most notably innate and innate-like lymphocytes such as NK, MAIT, and γδ T cells, but its ligands are typically only induced in tissues in response to stress.
“NKG2D is constitutively expressed on many immune cells, most notably innate and innate-like lymphocytes such as NK, MAIT, and γδ T cells, but its ligands are typically only induced in tissues in response to stress (20).”
From NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis (2023) · cites this paper as [20]
Upon NKG2D engagement, immune cells mediate cytotoxic responses and/or produce cytokines, and this receptor has been shown to play a role in many pathologies.
“Upon NKG2D engagement, immune cells mediate cytotoxic responses and/or produce cytokines, and this receptor has been shown to play a role in many pathologies (20,21).”
From NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis (2023) · cites this paper as [20]
NKG2D is expressed on NK cells, antigen experienced CD8 T cells and NKT cells and their engagement of its ligands leads to production of IFNγ, an archetype Th1 cytokine.
“NKG2D is expressed on NK cells, antigen experienced CD8 T cells and NKT cells and their engagement of its ligands leads to the production of IFNγ, an archetype Th1 cytokine (20,21,36).”
From NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis (2023) · cites this paper as [20]
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- Authors
- Jelenčić, V., Šestan, M., Kavazović, I., Lenartić, M., Marinović, S., Holmes, T. D., Prchal-Murphy, M., Lisnić, B., Sexl, V., Bryceson, Y. T., Wensveen, F. M., & Polić, B.
- Affiliations
- University of Rijeka (HR)
- Karolinska Institutet (SE)
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Polić, Bojan
- ORCID
- Venue
- Nature Immunology
- Published
- 2018-09-17
- Volume
- 19
- Issue
- 10
- Pages
- 1083-1092
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6166863
- OpenAlex
- W2890046609
- Cited by
- 62
- References
- 49
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 12 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 7 · 2018: 1
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-11-19)
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- NKG2D, NKp46, NK cell development, DAP12, CD3, interferon-gamma, tumor control, cytomegalovirus infection, NK cell education
- MeSH terms
- Animals, Antigens, Ly, Cytotoxicity, Immunologic, Killer Cells, Natural, Lymphocyte Activation, Mice, Knockout, Mice, Natural Cytotoxicity Triggering Receptor 1, NK Cell Lectin-Like Receptor Subfamily K
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