Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cellIg-like receptor two-domain short tail number 4

NK cells are cytotoxic to virus-infected and tumor cells that have lost sur face expression of class I MHC proteins. Target cell expression of class I MHC proteins inhibits NK cytotoxicity through binding to inhibitory NK rece ptors. In contrast, a similar family of activating NK receptors, characteri zed by the presence of a charged residue in their transmembrane portion and a truncated cytoplasmic tail, augment lysis by NK cells when ligated by an appropriate class I MHC protein. However, the class I MHC specificity of m any of these activating NK receptors is still unknown. Here, we show enhanc ed lysis of HLA-Cw4 but not HLA-Cw6-expressing cells, by a subset of NK clo nes. This subset may express killer cell Ig-like receptor two-domain short tail number 4 (KIR2DS4), as suggested by staining with various mAb. It is s till possible, however, that these clones may express receptors other than KIR2DS4 that might recognize HLA-Cw4. Binding of KIR2DS4-Ig fusion protein to cells expressing HLA-Cw4 but not to those expressing HLA-Cw6 was also ob served. The binding of KIR2DS4-Ig to HLA-Cw4 is weaker than that of killer cell Ig-like receptor two-domain long tail number 1 (KIR2DL1)-Ig fusion pro tein; however, such weak recognition is capable of inhibiting lysis by an N K transfectant expressing a chimeric molecule of KIR2DS4 fused to the trans membrane and cytoplasmic portion of KIR2DL1. Residue alpha 14 is shown to b e important in the KIR2DS4 binding to HLA-Cw4. Implications of the role of the activating NK receptors in immunosurveillance are discussed.