Porcine cells express more than one functional ligand for the human lymphocyte activating receptor NKG2D

Tran, Peter; Christiansen, Dale; Winterhalter, Adam; Brööks, Andrëw G.; Gorrell, Mark D.; Lilienfeld, Benjamin G.; Sandrin, Mauro S.; Sharland, Alexandra

doi:10.1111/j.1399-3089.2008.00489.x

Cited by 23 publications

(22 citation statements)

References 60 publications

(88 reference statements)

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“…1D). As observed previously, IL-2-cultured human NK cells lysed mock-infected SK cells to a significant extent, which is in line with the known xenogeneic response of human NK cells to porcine cells (48)(49)(50)(51). US3-null PRV-infected cells again showed higher susceptibility to NK cell-mediated lysis than wild-type or US3 rescue PRV-infected cells.…”

Section: Us3 Reduces Nk Cell-mediated Lysis Of Prv-infected Cellssupporting

confidence: 67%

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

Grauwet

Vitale

Pelsmaeker

et al. 2016

J Virol

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Section: Us3 Reduces Nk Cell-mediated Lysis Of Prv-infected Cellssupporting

confidence: 67%

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

Grauwet

Vitale

Pelsmaeker

et al. 2016

J Virol

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“…Many previously published studies demonstrated that inhibitory receptors on mature human NK cells were not able to recognize pig MHC molecules, while human NK activating receptors can recognize their ligands expressed on pig cells (18, 19, 44–46). If our observations in the rat-to-mouse model apply to human NK cells, reduced human NK cell responses to pig cells would be expected to be associated with global hyporesponsiveness in pig/human mixed chimeric mice.…”

Section: Discussionmentioning

confidence: 99%

Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model

Vishwasrao

Hölzl

et al. 2017

American Journal of Transplantation

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Mixed chimerism is a promising approach to inducing allograft and xenograft tolerance. Mixed allogeneic and xenogeneic chimerism in mouse models induced specific tolerance and global hyporesponsiveness, respectively, of host mouse NK cells. In this study, we investigated whether pig/human mixed chimerism could tolerize human NK cells in a humanized mouse model. Our results showed no impact of induced human NK cell reconstitution on porcine chimerism. NK cells from most pig/human mixed chimeric mice showed either specifically decreased cytotoxicity to pig cells or global hyporesponsiveness in an vitro cytotoxicity assay. Mixed xenogeneic chimerism did not hamper the maturation of human NK cells, but was associated with an alteration in NK cell subset distribution and IFN-γ production in the bone marrow. In summary, we demonstrate that mixed xenogeneic chimerism induces human NK cell hyporesponsiveness to pig cells. Our results support the use of this approach to inducing xenogeneic tolerance in the clinical setting. However, additional approaches are required to improve the efficacy of tolerance induction while assuring adequate NK cell functions.

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“…NKG2D can recognize several different ligands such as UL16-binding proteins and MICA/B in humans and Rae-1 family members and H60 in mice (35). Lilienfeld et al (23) identified porcine UL16-binding protein 1 as a functional predominant ligand for human NKG2D on PAEC, whereas further studies reported the possibility of more functional ligands in porcine renal epithelial and intestinal endothelial cells (24). It will be interesting to determine the nature and expression levels of the NKG2D ligands on PCC compared with PAEC in future studies to better understand their differences at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

“…Lilienfeld et al (23), using pig endothelial cells as target cells, identified porcine UL16-binding protein 1 as a functional predominant ligand for human NKG2D. However, further studies demonstrated the possibility of at least another functional ligand for human NKG2D in porcine renal epithelial and intestinal endothelial cells (24). Finally, costimulatory interactions such as that of pig CD86 with the CD28 variant expressed on human NK cells play a critical role in human NK cell triggering and are considered major targets for intervention (21,25,26).…”

mentioning

confidence: 99%

Multiple Receptors Trigger Human NK Cell-Mediated Cytotoxicity against Porcine Chondrocytes

Sommaggio

Cohnen

Watzl

et al. 2012

The Journal of Immunology

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Xenotransplantation of genetically engineered porcine chondrocytes may provide a therapeutic solution for the repair of cartilage defects of various types. However, the mechanisms underlying the humoral and cellular responses that lead to rejection of xenogeneic cartilage are not well understood. In this study, we investigated the interaction between human NK cells and isolated porcine costal chondrocytes (PCC). Our data show that freshly isolated NK cells adhere weakly to PCC. Consequently, PCC were highly resistant to cytolysis mediated by freshly isolated NK cells. However, the presence of human natural Abs in the coculture was often sufficient to trigger cytotoxicity against PCC. Furthermore, IL-2 stimulation of NK cells or activation of PCC with the proinflammatory cytokines TNF-α or IL-1α resulted in increased adhesion, which was paralleled by increased NK cell-mediated lysis of PCC. NK cell adhesion to PCC could be blocked by Abs against human LFA-1 and porcine VCAM-1. NKG2D and NKp44 were involved in triggering cytotoxicity against PCC, which expressed ligands for these activating NK cell receptors. Our data further suggest that NKp30 and NKp46 may contribute to the activation of NK cells by PCC under certain conditions. Finally, comparative studies confirmed that PCC are more resistant than porcine aortic endothelial cells to human NK cell-mediated lysis. Thus, the data demonstrate that human NK cells can kill pig chondrocytes and may therefore contribute to rejection of xenogeneic cartilage. In addition, we identify potential targets for intervention to prevent the NK cell response against pig xenografts.

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Porcine cells express more than one functional ligand for the human lymphocyte activating receptor NKG2D

Cited by 23 publications

References 60 publications

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model

Multiple Receptors Trigger Human NK Cell-Mediated Cytotoxicity against Porcine Chondrocytes

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