How inhibitory and activating C-lectin receptors operate in NK cells.

The C-type lectin receptors are disulfide-linked heterodimers of CD94 and NKG2 family members, either the inhibitory NKG2A or the activating NKG2C, and recognize the nonclassical MHC class I molecule HLA-E. Similar to KIRs with long cytoplasmic tails, ITIM-containing NKG2A signals through SHP-1/2 that mediate inhibitory signals. Likewise, NKG2C has a positively charged transmembrane domain that interacts with DAP-12 and transduces activating signals through Syk family members. In contrast, NKG2D is only distantly related to the other NKG2 family members, does not associate with CD94, and binds to the MHC-like ligands MICA, MICB, and ULBP family. Through its positively charged transmembrane domain NKG2D associates with the adaptor molecule DAP-10 that contains an YXNK motif to bind PI-3 kinase (PI3K) and send activating signals through this alternative pathway (see text for details). As the PI3K cascade is not inhibited by SHP-1/2, NKG2D may be able to mediate a dominant activation signal.