Natural Killer Cell Signaling

Natural killer cells are large granular lymphocytes that are important to the innate immune system. NK cell actions are controlled by a fine balance between activating and inhibiting pathways that are initiated upon interaction with target cells. Towards this function, NK cells express an array of cell surface receptors that fall into two categories:Activating receptors like NKp30, NKp44 and NKp46 initiate protein tyrosine kinase (PTK)-dependent pathways through non-covalent associations with adapters CD3ζ and Fc ε RI γ that have ITAMs (immunoreceptor tyrosine-based activation motifs). Upon receptor activation, these adapters recruit tyrosine kinases SYK and ZAP70. Receptors like NKG2D associate with adapter DAP10 that does not contain an ITAM and signals via PLC-γ2. Signal transduction via activating receptors ultimately leads to cytolytic activity and cytokine production.Inhibitory cell surface receptors are characterized by intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). They act by antagonizing the activating pathways through protein tyrosine phosphatases (PTPs). Several signaling components are substrates for the PTKs of the activating receptors and the PTPs of the inhibitory receptors. Such common substrates include LAT, SLP-76, SYK and ZAP70. Phosphorylation status of these molecules determines the activating/inhibiting outcome. (Upgraded 01/2020)