An inhibitory signal is delivered to natural killer (NK) cells and a subset of cytotoxic 1 cells upon recognition of HLA class I molecules on target cells. We demonstrate that soluble forms of killer cell inhibitory receptors (KIR) bind directly and specifically to HLA-Calleles on transfected cells. Furthermore, transfer of Individual KIR into NK clones reconstituted recognition of HLA-C on target cells, leading to inhibition of lysis. Using such functional reconstitution, a related KIR that confers specificity for some HLA-B alleles was also identified. These KIR share consewed tyrosine phosphorylation motifs in their cytoplasmic tells. Thus, a single receptor in NK cells provides both specificity for HLA class I on target cells and the inhibitory signal that prevents lysis. introduction

Natural killer (NK) cells kill virus-infected cells (Biron et al., 1989; Malnati et al., 1993; Brutkiewicz and Welsh, 1995) and contribute to the rejection of bone marrow alloor xenografts (Vu et al., 1992; Murphy et al., 1993). They also play an important regulatory role in immune responses to parasites and bacteria (Scott and Trinchieri, 1995). Despite their lack of immunoglobulin and T cell antigen receptors (TCR), NK cells display specificity in target cell recognition. In contrast with T cells, the specificity of target cell recognition by NK cells is not provided by triggering receptors but by inhibitory receptors associated with recognition of major histocompatibility complex (MHC) class I molecules (Yokoyama, 1995; Lanier and Phillips, 1995; Leibson, 1995; Raulet and Held, 1995). The importance of peptides bound to class I molecules for proper recognition by NK ceils suggests that the same type of stably assembled class I complex of heavy chain, 82-microglobulin, and peptide is recognized by NK and T cells (Correa and Raulet, 1995; Malnati et al., 1995). Target cells that fail to express MHC class I molecules, or properly assembled MHC class I molecules, are generally lysed by NK cells (Storkus et al., 1989; Ljunggren et al., 1989; Ljunggren and KBrre, 1990; Liao et al., 1991). Thus, the outcome of MHC class I recognition is totally different for cytotoxic T cells and NK cells. Whereas class l-restricted CD8+ T cells are triggered to kill target cells that express a given class I molecule, NK cells receive a negative signal