Molecular mechanisms of natural killer cell activation

With an array of activating and inhibitory receptors, natural killer (NK) cells can specifically eradicate infected and transformed cells. Target cell killing is achieved through directed release of lytic granules. Recognition of target cells also induces production of chemokines and cytokines that can coordinate immune responses. Upon contact with susceptible cells, a multiplicity of activating receptors can induce signals for adhesion. Engagement of the integrin leukocyte functional antigen-1 mediates firm adhesion, provides signals for granule polarization and orchestrates the structure of an immunological synapse that facilitates efficient target cell killing. Other activating receptors apart from leukocyte functional antigen-1 signal for lytic granule exocytosis, a process that requires overcoming a threshold for activation of phospholipase C-γ, which in turn induces STIM1- and ORAI1-dependent store-operated Ca²+ entry as well as exocytosis mediated by the SNARE-containing protein syntaxin-11 and regulators thereof. Cytokine and chemokine release follows a different secretory pathway which also requires phospholipase C-γ activation and store-operated Ca²+ entry. Recent studies of human NK cells have provided insights into a hierarchy of effector functions that result in graded responses by NK cell populations. Responses display cellular heterogeneity and are influenced by environmental cues. This review highlights recent knowledge gained on the molecular pathways for and regulation of NK cell activation.