NKp46 modulates NK immune synapse function (INC6P. 346)

Natural killer cells play an important role in the first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell-surface expressed inhibitory and activating receptors. NKp46 is a major NK cell activating receptor that is involved in the elimination of viral infected cells. NKp46 also regulates interactions with other immune cells including T cells and dendritic cells. Recent studies revealed that complex integration of NK receptor signaling controls the cytoskeleton rearrangement and other immune synapse related events. However the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study we found that NKp46 forms microcluster structures at the immune synapse between NK cells and target cells. Labeling of F-actin showed that higher expression of NKp46 is correlated with increased accumulation of actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary NK cells abridged recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granule polarization to the immune synapse. Taken together, our data suggests that NKp46 signaling directly effects both the early formation and late function of the NK lytic immune synapse. Moreover, this is a continuous rather than threshold effect of activation vs non-activation.