Natural killer (NK) cell activation is controlled by the integration of signals from activation and inhibitory receptors. (a) Inhibitory NK cell receptors recognize self MHC class I and restrain NK cell activation. (b) When unimpeded by the inhibitory receptors, binding of NK cell activation receptors to their ligands on target cells results in NK cell stimulation. In the absence or downregulation of self MHC class I on the target cells, these stimulatory signals are no longer suppressed, resulting in NK cell responses including cytokine production and granule release leading to cytotoxicity. Note that this model indicates that NK cells do not kill by default; that is, when MHC class I inhibition is absent, the NK cell must still be stimulated through activation receptors. Moreover, whether or not an individual NK cell is activated by a target is determined by this complex balance of receptors with opposing function and expression of the corresponding ligands. In general, however, inhibition dominates over activation. Finally, NK cells can be directly stimulated by cytokines such as interleukin-12 that trigger the production of other cytokines by NK cells (not shown). These direct cytokine-mediated responses are not affected by MHC class I expression.