A spontaneous mutation in NCR1 locus reveals an inhibitory role for IFNγ response by NCR1 via inhibiting dok-1 phosphorylation

Abstract Immunosurveillance by Natural killer (NK) cells provides an efficient effector mechanism to eliminate tumor and virally infected cells. A well-defined characteristic of NK cells is their ability to lyse target cells deficient in MHC class I expression or target cells that express non-MHC ligands as a result of infection or transformation. This observation has been the basis for identification of a number of inhibitory and activatory NK cell receptors. Although the collective effort during the last decade shed light on the function of many NK cell receptors, the role of NCR1 in NK cell biology remains highly controversial. We have recently identified a spontaneous mutation of NCR1 in our C57BL/6 mouse colony. In this mutant, NCR1 expression was absent on conventional NK cells of all lymphoid organs as well as on innate lymphocytes (ILC3) of the gut lamina propria. Of note, NCR1 expression was absent on the surface as well as in the intracellular compartment of NK cells. Likewise, lack of NCR1 expression was confirmed in mixed BM chimera indicating a cell intrinsic phenotype. Only genetic backcrossing could correct the lack of NCR1 in these mice. ORF sequencing of NCR1 gene in mutant mice revealed a point mutation (C14R) in the region of signal peptide of NCR1 protein. However, while development and homeostasis of NK cells was not affected by the lack of NCR1, infection of NCR1C14R mutant mice with murine cytomegalovirus resulted in increased resistance, an advantage that correlated with NK cell hyperresponsive production of IFN-γ, but not cytotoxic activity. Moreover, NCR1 limits NK cell IFNγ response via regulation of Dok-1 phosphorylation and p38 activation. Collectively, our data reveal the role for NCR1 in IFNγ production of NK cell.