A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).
There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.
In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1.