Question

NK cells express several receptors that have intracellular domains of either ITAMs or ITIMs. Based on these domains with differing purposes, when do NK cells become activated to kill a target cell? What could be different about a cancer cell that causes it to be targeted by an NK cell? What could be different about virally-infected cells that causes it to be a target?

Answer 1

When receptors with immunoreceptor tyrosine-based activation motif (ITAM) are triggered,  NK cells are actvated to kill target cells. When receptors with immunoreceptor tyrosine-based inhibitory motif–dependent (ITIM) are triggered, NK cells are inhibited.The activation of NK cells is regulated through the integration of signals from a number of inhibitory and activating receptors.

Normal healthy cells express MHC class I molecules on their surface which act as ligands for inhibitory receptors and contribute to the self-tolerance of NK cells.Cancer cells lack MHC class I molecules on their surface leading to lower inhibitory signal in NK cell. Simultaneously, cellular stress associated with tumor development such as DNA damage response and tumor suppressor genes upregulate ligands for activating receptors in these cells. As a result, the signal from activating receptors in NK cell shifts the balance toward NK cell activation and elimination of target cells directly through NK cell-mediated cytotoxicity or indirectly through secretion of pro-inflammatory cytokines.

Viral infected cells express viral-derived products or viral peptide-loaded MHC molecules which are recognized by NK cell. Simultaneously, host stress molecules such as interferons released by viral infected cells up regulate ligands for activating receptors in NK cell. As a result, the signal from activating receptors in NK cell results in elimination of virus infected cells.