NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion.
Natural killer (NK) cell sense virally infected cells and tumor cells through multiple cell surface receptors. Many NK cell-activating receptors signal through immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters, which trigger both cytotoxicy and secretion of interferon-gamma (IFN-gamma). Within the ITAM pathway, distinct signaling intermediates are variably involved in cytotoxicity and/or IFN-gamma secretion. In this study, we have evaluated the role of protein kinase C- (PKC-) in NK-cell secretion of lytic mediators and IFN-gamma. We found that engagement of NK-cell receptors that signal through ITAMs results in prompt activation of PKC-. Analyses of NK cells from PKC--deficient mice indicated that PKC- is absolutely required for ITAM-mediated IFN-gamma secretion, whereas it has no marked influence on the release of cytolytic mediators. Moreover, we found that PKC- deficiency preferentially impairs sustained extracellular-regulated kinase signaling as well as activation of c-Jun N-terminal kinase and the transcription factors AP-1 and NFAT but does not affect activation of NF-kappaB. These results indicate that NK cell-activating receptors require PKC- to generate sustained intracellular signals that reach the nucleus and promote transcriptional activation, ultimately inducing IFN-gamma production.
Tassi
Ilaria
I
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Cella
Marina
M
Presti
Rachel
R
Colucci
Angela
A
Gilfillan
Susan
S
Littman
Dan R
DR
Colonna
Marco
M
D000818:Animals; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism
D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D018808:Transcription Factor AP-1; D007371:Interferon-gamma; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048031:JNK Mitogen-Activated Protein Kinases
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