NK cell-activating receptors require PKC-θ for sustained signaling, transcriptional activation, and IFN-γ 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-theta (PKC-theta) 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-theta. Analyses of NK cells from PKC-theta-deficient mice indicated that PKC-theta 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-theta 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-kappa B. These results indicate that NK cell-activating receptors require PKC-theta to generate sustained intracellular signals that reach the nucleus and promote transcriptional activation, ultimately inducing IFN-gamma production. (Blood. 2008; 112: 4109-4116)