Specific recognition of HLA-E, but not classical, HLA class I molecules bysoluble CD94/NKG2A and NK cells

The CD94/NKG2 receptors expressed by subpopulations of NK cells and T cells have been implicated as receptors for a broad range of both classical and nonclassical HLA class I molecules. To examine the ligand specificity of CD 94/NKG2 proteins, a soluble heterodimeric form of the receptor was produced and used in direct binding studies with cells expressing defined HLA class I/peptide complexes. We confirm that CD94/NKG2A specifically interacts wit h HLA-E and demonstrate that this interaction is dependent on the associati on of HLA-E with peptide. Moreover, no interaction between CD94/NKG2A and c lassical HLA class I molecules was observed, as assayed by direct binding o f the soluble receptor or by functional assays using CD94/NKG2A(+) NK cells . The role of the peptide associated with HLA-E in the interaction between HLA-E and CD94/NKG2A was also assessed. All class I leader sequence peptide s tested bound to HLA-E and were recognized by CD94/NKG2A, However, amino a cid variations in class I reader sequences affected the stability of HLA-E, Additionally, not all HLA-E/peptide complexes examined were recognized by CD94/NKG2A, Thus CD94/NKG2A recognition of HLA-E is controlled by peptide a t two levels; first, peptide must stabilize HLA-E and promote cell surface expression, and second, the HLA-E/peptide complex must form the ligand for CD94/NKG2A.