MOLECULAR-CLONING OF NKP46 - A NOVEL MEMBER OF THE IMMUNOGLOBULIN SUPERFAMILY INVOLVED IN TRIGGERING OF NATURAL CYTOTOXICITY

NKp46 has been shown to represent a novel, natural killer (NK) cell-sp ecific surface molecule, involved in human NK cell activation. In this study, we further analyzed the role of NKp46 in natural cytotoxicity against different tumor target cells. We provide direct evidence that NKp46 represents a major activating receptor involved in the recogniti on and lysis of both human and murine tumor cells. Although NKp46 may cooperate with other activating receptors (including the recently iden tified NKp44 molecule) in the induction of NK-mediated lysis of human tumor cells, it may represent the only human NK receptor involved in r ecognition of murine target cells. Molecular cloning of the cDNA encod ing the NKp46 molecule revealed a novel member of the immunoglobulin ( Ig) superfamily, characterized by two C2-type Ig-like domains in the e xtracellular portion. The transmembrane region contains the positively charged amino acid Arg, which is possibly involved in stabilizing the association with CD3 zeta chain. The cytoplasmic portion, spanning 30 amino acids, does not contain immunoreceptor tyrosine-based activatin g motifs. Analysis of a panel of human/hamster somatic cell hybrids re vealed segregation of the NKp46 gene on human chromosome 19. Assessmen t of the NKp46 mRNA expression in different tissues and cell types una mbiguously confirmed the strict NK cell specificity of the NKp46 molec ule. Remarkably, in line with the ability of NKp46 to recognize ligand (s) on murine target cells, the cDNA encoding NKp46 was found to be ho mologous to a cDNA expressed in murine spleen. In conclusion, this stu dy reports the first characterization of the molecular structure of a NK-specific receptor involved in the mechanism of NK cell activation d uring natural cytotoxicity.