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Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages

Abstract

Natural killer (NK) cells attack tumor and infected cells, but the receptors and ligands that stimulate them are poorly understood. Here we report the expression cloning of two murine ligands for the lectin-like receptor NKG2D. The two ligands, H-60 and Rae1β, are distant relatives of major histocompatibility complex class I molecules. NKG2D ligands are not expressed by most normal cells but are up-regulated on numerous tumor cells. We show that mouse NKG2D is expressed by NK cells, activated CD8+ T cells and activated macrophages. Expression of either NKG2D ligand by target cells triggers NK cell cytotoxicity and interferon-γ secretion by NK cells, as well as nitric oxide release and tumor necrosis factor α transcription by macrophages. Thus, through their interaction with NKG2D, H-60 and Rae1β are newly identified potent stimulators of innate immunity.

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Figure 1: Numerous tumor cells express ligands for mNKG2D.
Figure 2: BALB/c thymocytes and stimulated splenocytes express ligands for mNKG2D.
Figure 3: The MHC I–related molecules Rae1β and H-60 are ligands for mNKG2D.
Figure 4: The NKG2D receptor is expressed on freshly isolated and IL-2–activated NK cells, CD8+ T cells and LPS-stimulated macrophages.
Figure 5: NKG2D mRNA is expressed in naïve NK cells, activated CD8+ T cells and LPS-stimulated macrophages.
Figure 6: Expression of Rae1 or H-60 induces target cell killing and IFN-γ production by NK cells.
Figure 7: Expression of Rae1 or H-60 induces nitric oxide production and TNF-α transcription in stimulated peritoneal macrophages.

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Acknowledgements

We thank R.E.Vance and C.W. McMahon for advice and comments on the manuscript, J. Egen for help with the immunofluorescence staining, H. Nolla for cell sorting, C.White for expert technical assistance, J.F. Elliott, M. Fasso, L. Mendoza for their gifts of reagents and cell lines. Supported by grants from the National Institute of Health (D.H.R.) and the Deutsche Forschungsgemeinschaft (A.D.). A.D. is a Physician Postdoctoral fellow of the Howard Hughes Medical Institute.

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Correspondence to David H. Raulet.

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Diefenbach, A., Jamieson, A., Liu, S. et al. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol 1, 119–126 (2000). https://doi.org/10.1038/77793

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