NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Siemaszko, Jagoda; Marzec-Przyszlak, Aleksandra; Bogunia‐Kubik, Katarzyna

doi:10.3390/cells10061420

Cited by 41 publications

(21 citation statements)

References 185 publications

(249 reference statements)

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“…We are aware that our results need to be interpreted with caution, but our results may provide a valuable basis for large, adequately powered studies designed to include granular endpoints, such as the results of sequential surveillance biopsies, in order to clarify the actual role of genetically determined NKG2C expression and functionality as a risk factor for NK cell-driven alloimmune injury in kidney transplant recipients. In this context, a comprehensive, combined analysis including different genetic determinants of NK cell activity, in addition to functional NKG2C and FcγRIIIA gene variants, such as KIR-ligand mismatches or polymorphisms/haplotypes determining the functionality of other important receptors ( 42 ), would contribute significantly to a better understanding of NK cell biology in transplant medicine.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

et al. 2022

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Natural killer (NK) cells may contribute to antibody-mediated rejection (ABMR) of renal allografts. The role of distinct NK cell subsets in this specific context, such as NK cells expressing the activating receptor NKG2C, is unknown. Our aim was to investigate whether KLRC2 gene deletion variants which determine NKG2C expression affect the pathogenicity of donor-specific antibodies (DSA) and, if so, influence long-term graft survival. We genotyped the KLRC2wt/del variants for two distinct kidney transplant cohorts, (i) a cross-sectional cohort of 86 recipients who, on the basis of a positive post-transplant DSA result, all underwent allograft biopsies, and (ii) 1,860 recipients of a deceased donor renal allograft randomly selected from the Collaborative Transplant Study (CTS) database. In the DSA+ patient cohort, KLRC2wt/wt (80%) was associated with antibody-mediated rejection (ABMR; 65% versus 29% among KLRC2wt/del subjects; P=0.012), microvascular inflammation [MVI; median g+ptc score: 2 (interquartile range: 0-4) versus 0 (0-1), P=0.002], a molecular classifier of ABMR [0.41 (0.14-0.72) versus 0.10 (0.07-0.27), P=0.001], and elevated NK cell-related transcripts (P=0.017). In combined analyses of KLRC2 variants and a functional polymorphism in the Fc gamma receptor IIIA gene (FCGR3A-V/F158), ABMR rates and activity gradually increased with the number of risk genotypes. In DSA+ and CTS cohorts, however, the KLRC2wt/wt variant did not impact long-term death-censored graft survival, also when combined with the FCGR3A-V158 risk variant. KLRC2wt/wt may be associated with DSA-triggered MVI and ABMR-associated gene expression patterns, but the findings observed in a highly selected cohort of DSA+ patients did not translate into meaningful graft survival differences in a large multicenter kidney transplant cohort not selected for HLA sensitization.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

et al. 2022

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“…NK cells play an important role in regulating liver fibrosis. The binding of NK cell receptors such as NKG2D and NKp46 with the corresponding ligands on the surface of HSCs stimulates the antifibrotic activity of NK cells [9,21,22]. NK cells induce HSC apoptosis not only through direct contact between cells but also through the production of IFN-γ [10] or expression of apoptosis-related ligands such as FASL and TRAIL [23], or they directly kill HSCs by releasing Prf and Gzmb [24].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…NK cells constitute a major subset of hepatic non-parenchymal cells, accounting for 10%-15% of hepatic lymphocytes in mice and 30%-50% in humans and rats [7,8]. A previous study reports that NK cells killed activated HSCs by producing interferon (IFN)-γ, interacted with RAE-1 through NKG2D to destroy HSCs, or induced their apoptosis, thus inhibiting liver fibrosis [9]. NK cells have also been reported to inhibit liver fibrosis caused by the hepatitis virus [10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis

et al. 2023

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Schistosomiasis is a zoonotic parasitic disease. Schistosoma japonicum eggs deposited in the liver tissue induce egg granuloma formation and liver fibrosis, seriously threatening human health. Natural killer (NK) cells kill activated hepatic stellate cells (HSCs) or induce HSC apoptosis and inhibit the progression of liver fibrosis. However, the function of NK cells in liver fibrosis caused by S. japonicum infection is significantly inhibited. The mechanism of this inhibition remains unclear. Twenty mice were percutaneously infected with S. japonicum cercariae. Before infection and 2, 4, 6, and 8 weeks after infection, five mice were euthanized and dissected at each time point. Hepatic NK cells were isolated and transcriptome sequenced. The sequencing results showed that Tigit expression was high at 4–6 weeks post infection. This phenomenon was verified by reverse transcription quantitative PCR (RT-qPCR) and flow cytometry. NK cells derived from Tigit-/- and wild-type (WT) mice were co-cultured with HSCs. It was found that Tigit-/- NK cells induced apoptosis in a higher proportion of HSCs than WT NK cells. Schistosomiasis infection models of Tigit-/- and WT mice were established. The proportion and killing activity of hepatic NK cells were significantly higher in Tigit-/- mice than in WT mice. The degree of liver fibrosis in Tigit-/- mice was significantly lower than that in WT mice. NK cells were isolated from Tigit-/- and WT mice and injected via the tail vein into WT mice infected with S. japonicum. The degree of liver fibrosis in mice that received NK cell infusion reduced significantly, but there was no significant difference between mice that received NK cells from Tigit-/- and WT mice, respectively. Our findings indicate that Tigit knockout enhanced the function of NK cells and reduced the degree of liver fibrosis in schistosomiasis, thus providing a novel strategy for treating hepatic fibrosis induced by schistosomiasis.

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“…The NKG2D receptor binds to eight stress-induced ligands present on the cell surface, which are split into two families: the MHC class I chainrelated protein (MIC) family, which includes MICA and MICB, and the UL16-binding protein (ULBP) family, which includes ULBP1-6. These ligands are overexpressed in tumor cells (33), making NKG2D-mediated recognition a prominent pathway by which NK cells identify and kill transformed cells (34). Moreover, because the expression of NKG2D ligands also enhances the cytotoxic activity of NK cells towards virus-infected cells, different viruses have developed unique mechanisms to manipulate the expression of stress-induced ligands to evade NK-mediated elimination (32,(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Khaleafi,

Zeleznjak,

Cordela

et al. 2023

Front. Immunol.

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In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response.

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NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Cited by 41 publications

References 185 publications

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

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