Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells

Natural killer (NK) cells destroy virus-infected and tumour cells, apparent ly without the need for previous antigen stimulation(1). In part, target ce lls are recognized by their diminished expression of major histocompatibili ty complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface(2-8). NK cells also express triggering re ceptors that are specific for non-MHC ligands; but the nature of the ligand s recognized on target cells is undefined(9-14). NKp46 is thought to be the main activating receptor for human NK cells(9,15). Here we show that a sol uble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin o f influenza virus and the haemagglutinin-neuraminidase of parainfluenza vir us. In a substantial subset of NK cells, recognition by NKp46 is required t o lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent wit h the known sialic binding capacity of the viral glycoproteins. These findi ngs indicate how NKp46-expressing NK cells may recognize target cells infec ted by influenza or parainfluenza without the decreased expression of targe t-cell MHC class I protein.