Natural kiUer (NK) cell dones have been previously described which are inhibited by HLA-C aUdes with Asn77-LysS0 (NK1-specific cdls) or by HLA-C alldes with Ser77-Asn80 (NK2- specific ceils). In the present work, the generation of NK cells with HLA-B-rdated spedficities was attempted by stimulation of a Bw4 homozygous responder by a Bw6 homozygous donor. Two NK clones were found, which were inhibited by HLA-Bw4 (but not by HLA-Bw6) allotypes and by some HLA-A allotypes that share the Bw4 public epitope. Inhibition of NK cell-mediated lysis strongly correlated with the presence of an Ile residue at position 80 of the protective allele. These NK cell clones define a new specificity termed NK3.