Regulation of NK cell response by activating and inhibitory receptors.

Inhibitory receptors (eg, inhibitory KIR, CD94/NKG2A) recognize and engage their ligands, MHC class I molecules (HLA), on the surface of the target tumor cell, thereby initiating an inhibitory signal. Activating receptors (eg, activating KIR, CD94/NKG2C, NKG2D) bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. (A) When inhibitory receptors engage HLA in the absence of an activating receptor/ligand interaction, a net negative signal is generated, resulting in no target cell lysis. (B) Conversely, when activating receptors engage their ligands on target cells in the absence of inhibitory receptor/ligand interaction, a net activation signal is generated, resulting in target cell lysis. This scenario is likely operative in NK alloreactivity in the setting of KIR epitope mismatch (see Figure 4 and text for more details). More complex physiologic scenarios are shown in C and D with both inhibitory and activating receptor/ligand signals being generated when an NK cell interacts with a target cell. (C) Here, the activating receptor/ligand interactions predominate over weaker inhibitory receptor/ligand signals with the net result of NK cell activation and target cell lysis. This net result may occur when activation receptors and ligands are up-regulated, thereby amplifying the net activation signal to exceed the inhibitory signal. For example, the activating ligands MICA/B and ULBPs are expressed highly in stressed or transformed cells, thereby activating NKG2D/PI3K pathways that are not susceptible to inhibitory signals (see text for details). Alternatively, when expression of self-MHC class I ligands is decreased in the setting of viral infection or transformation, the net signal may be positive, also resulting in target cell lysis. (D) Here, inhibitory receptor/ligand interactions result in a net negative signal that prevents NK cell lysis of the target cell. This process may occur constantly as NK cells survey normal host tissues. Not shown is the scenario of absence of both inhibitory and activating signals that results in no NK cell activation.