The activating receptor NKp46 is essential for the development of type 1 diabetes

Gur, Chamutal; Porgador, Angel; Elboim, Moran; Gazit, Roi; Mizrahi, Sa’ar; Stern-Ginossar, Noam; Achdout, Hagit; Ghadially, Hormas; Dor, Yuval; Nir, Tomer; Doviner, Victoria; Hershkovitz, Oren; Mendelson, Michal; Naparstek, Yaakov; Mandelboim, Ofer

doi:10.1038/ni.1834

Cited by 159 publications

(227 citation statements)

References 36 publications

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“…Infected islets were dominated by NK cell infiltration but beta cell function appeared to be preserved. A recent study by Gur and colleagues identified beta cell ligands for the activating NK cell receptor Nkp46 in human and murine pancreas that were shown to be responsible for diabetes development in the NOD mouse [37]. More functional studies of NK cells in early-onset type 1 diabetes are required to determine the effects of the genetic associations described here.…”

Section: Discussionmentioning

confidence: 99%

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

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Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

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Section: Discussionmentioning

confidence: 99%

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

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“…Among the NK cell killer receptors, the NCRs NKp30, NKp44, and NKp46/NCR1, which were discovered more than a decade ago (4), were shown to be paramount to many immunological processes. Specifically, NKp46/NCR1 was implicated in influenza (7,8), tumorigenesis (13), and diabetes (27,28). However, remarkably, other than the influenza virus HA (7) and the pox virus HA (29), no ligands for this important receptor were identified.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the ligand on MCA-transformed cells undergoes immune editing by NKp46/NCR1 pressure (14), whereas the ligand on D122 cells described in this study apparently does not. Finally, we have recently shown that a ligand for NKp46/NCR1 is expressed by human and mouse b cells (27,28), and it was also demonstrated that upon human CMV infection of dendritic cells, an unknown ligand of NKp46/NCR1 is downregulated to prevent NK cell-mediated lysis of the infected dendritic cells (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

The Journal of Immunology

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147

119

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NK cells employ a variety of activating receptors to kill virally infected and tumor cells. Prominent among these receptors are the natural cytotoxicity receptors (NCRs) (NKp30, NKp44, and NKp46), of which only NKp46 has a mouse ortholog (NCR1). The tumor ligand(s) of NKp46/NCR1 is still unknown, but it was shown that the human NKp46 and the mouse NCR1 are involved in tumor eradication both in vitro and in vivo. Whether any of the NK activating receptors is involved in the prevention of tumor metastasis is unknown. To address this question, we studied the activity of the NK cell receptor NKp46/NCR1 in two spontaneous metastasis models, the B16F10.9 melanoma (B16) and the Lewis lung carcinoma (D122) in the NCR1 knockout mouse that was generated by our group, in various in vitro and in vivo assays. We demonstrated that all B16 and D122 tumors, including those generated in vivo, express an unknown ligand(s) for NKp46/NCR1. We have characterized the properties of the NKp46/NCR1 ligand(s) and demonstrated that NKp46/NCR1 is directly involved in the killing of B16 and D122 cells. Importantly, we showed in vivo that NKp46/NCR1 plays an important role in controlling B16 and D122 metastasis. Thus, to our knowledge, in this study we provide the first evidence for the direct involvement of a specific NK killer receptor in preventing tumor metastasis.

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“…The emerging role of NKp46 is highlighted in studies on mice deficient for Ncr1. These knock-out mice are unable to fight influenza infection, unable to control a specific experimental lymphoma model, and are more protected from development of type 1 diabetes (7)(8)(9).…”

mentioning

confidence: 99%

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

Lai

Mager

2012

Journal of Biological Chemistry

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The activating receptor NKp46 is essential for the development of type 1 diabetes

Cited by 159 publications

References 36 publications

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

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