LLT1-mediated activation of IFN-gamma production in human natural killer cells involves ERK signalling pathway.
Natural killer (NK) cell functions are regulated by a delicate balance of signals received through activating and inhibitory receptors expressed on the cell surface. Lectin-like transcript-1 (LLT1), expressed on a subpopulation of NK cells and other immune cells is a ligand for the NK cell inhibitory receptor, NKR-P1A (CD161). Previous studies showed that cross-linking surface LLT1 with a monoclonal antibody stimulated NK cell IFN-gamma secretion but had no effect on cytotoxicity. Here, we have examined the signalling pathways associated with LLT1-stimulated IFN-gamma secretion. We ligated LLT1 on NK92 cells with CD161 on target cells and analysed IFN-gamma production in the presence of pharmacological inhibitors specific for various signalling mechanisms. These results indicate that LLT1 employs Src-PTK, p38 and ERK signalling pathways, but not PKC, PI3K or calcineurin. Phosphorylation studies of the signalling adaptor molecules confirmed that the ERK signalling pathway is associated with LLT1-mediated IFN-gamma production. LLT1 ligation is not associated with any change in detectable IFN-gamma mRNA levels suggesting that LLT1-stimulated IFN-gamma production in NK cells may involve post-transcriptional or translational events.
Bambard
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Department of Molecular Biology and Immunology and Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, USA.
Mathew
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SO
Mathew
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PA
D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology*; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology
C400041:CLEC2D protein, human; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011956:Receptors, Cell Surface; D007371:Interferon-gamma; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases