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Natural Cytotoxicity Receptors (NCRs) and Ligands

Natural cytotoxicity receptors (NCRs) are expressed almost exclusively by natural killer (NK) cells and play a central role in triggering their activation. In humans, NKp30, NKp46, and NKp80 are constitutively expressed on resting and activated NK cells, while NKp44 expression is induced following activation. Mouse NK cells also express NKp46, but NKp80 is absent in rodents as are orthologues of NKp30 and NKp44 in many commonly used mouse strains. Ligands of the NCRs include viral hemagglutinins, which have been reported to bind to NKp30, NKp44, and NKp46 and Activation-induced C-type Lectin (AICL), which serves as a ligand for NKp80. Most tumor-associated ligands of the NCR family are unknown, but recent studies demonstrated that B7-H6 and BAG6, which are expressed on multiple tumor cell lines, bind to NKp30 and trigger NK cell activation. NKp30 and NKp46 promote NK cell activation through their association with the immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins, CD3 zeta and FcRgamma, while NKp44 signals through Dap12.