Recognition by natural killer (NK) cells of major histocompatibility c
omplex (MHC) class I molecules on target cells inhibits NK-mediated ly
sis. Here, inhibition of NK clones by HLA-B2705 molecules mutated at
single amino acids in the peptide binding site varied among HLA-B2705
-specific NK clones. In addition, a subset of such NK clones was inhib
ited by only one of several self peptides loaded onto HLA-B2705 molec
ules expressed in peptide transporter-deficient cells, showing that re
cognition was peptide-specific. These data demonstrate that specific s
elf peptides, complexed with MHC class I, provide protection from NK-m
ediated lysis.