Natural killer (NK) cells destroy virus-infected and tumor cells without pr
ior antigen, stimulation. The NK cell cytotoxicity is regulated in large pa
rt by the expression of NK cell receptors that are able to bind major histo
compatibility complex (MHC) class I glycoproteins. NK cells also express ly
sis triggering receptors specific for non-MHC ligands, including NKp30, NKp
44, NKp46 and CD16. However, the nature of their ligands, recognized on tar
get cells, is undefined. We have recently shown that the NKp46 protein, but
not the CD16 protein, recognizes the hemagglutinin (HA) of influenza virus
(IV) and the hemagglutinin-neuraminidase (HN) of Sendai virus (SV), and th
at the recognition of HA from IV requires the sialylation of NKp46 oligosac
charides. We have also demonstrated that binding of NKp46 to HA of IV is re
quired for lysis of cells expressing the corresponding glycoproteins by a s
ubstantial subset of NK clones. Here we show that NKp44, but not NKp30, can
also recognize the HA of both IV and SV and that the recognition of IV HA
requires the sialylation of the NKp44 receptor in a similar way to that of
NKp46. SV infection of 721.221 cells expressing MHC class I proteins result
ed in the abrogation of the inhibition by NK clones expressing high levels
of NKp44. In addition, the binding of NKp44 to HA improves the ability of s
ome NK clones to lyse IV infected cells.