How inhibitory and activating KIR operate on NK cells.

KIR receptors have either 2 or 3 immunoglobulin domains (2D or 3D) and a long (L) cytoplasmic tail containing ITIM motifs or a short (S) cytoplasmic tail and positively charged transmembrane domain that interacts with the ITAM-containing adaptor molecule DAP-12. When inhibitory KIRs bind their HLA ligand, src family kinases phosphorylate the ITIM, allowing binding of the tyrosine phosphatase SHP-1 (and possibly SHP-2) through its SH2 domain. SHP-1 is able to dephosphorylate multiple targets in the ITAM-activating pathway, thereby mediating its negative signal. In contrast, when activating KIRs are ligated, src family kinases phosphorylate the ITAM-containing adaptor molecule DAP-12 that, in turn, binds to and activates the Syk family tyrosine kinases that trigger the downstream activation cascade. As inhibitory KIRs have higher affinity for the MHC class I ligands, coligation of both activating and inhibitory receptors results in a net negative signal, and no activation of the NK cell's cytotoxic or cytokine-secreting programs.