HLA-E IS A MAJOR LIGAND FOR THE NATURAL-KILLER INHIBITORY RECEPTOR CD94 NKG2A/

We previously showed that the availability of a nonamer peptide derive d from certain HLA class I signal sequences is a necessary requirement for the stabilization of endogenous HLA-E expression on the surface o f 721.221 cells. This led us to examine the ability of HLA-E to protec t HLA class I transfectants from natural killer (NK) cell-mediated lys is, It was possible to implicate the CD94/NKG2A complex as an inhibito ry receptor recognizing this class Ib molecule by using as target a .2 21 transfectant selectively expressing surface HLA-E. HLA-E had no app arent inhibitory effect mediated through the identified Ig superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1, Further studies of CD94/NKG2+ NK cell-mediated recognition of .221 cells trans fected with different HLA class I allotypes (i.e., -Cw4, -Cw3, -B7) co nfirmed that the inhibitory interaction was mediated by CD94/NKG2A rec ognizing the surface HLA-E molecule, because only antibodies directed against either HLA-E, CD94, or CD94/NKG2A specifically restored lysis, Surface stabilization of HLA-E in cold-treated .221 cells loaded with appropriate peptides was sufficient to confer protection, resulting f rom recognition of the HLA class Ib molecule by the CD94/NKG2A inhibit ory receptor. Consistent with the prediction that the ligand for CD94/ NKG2A is expressed ubiquitously, our examination of HLA-E antigen dist ribution indicated that it is detectable on the surface of a wide vari ety of cell types.