The binding site of NK receptors on HLA-C molecules

The protection of cells expressing class I HLA molecules from NK lysis is mediated by natural killer cell inhibitory receptors (NKIR). Using site-directed mutagenesis, residues on HLA-C that determine the locus specificity (alpha Val-76), allotype group specificity (a dimorphism alpha Asn-80/Lys-80), and affinity of NKIR binding (a second pair of dimorphisms, alpha Ala-73, Asp-90 or alpha Thr-73, Ala-90) have been identified. Thus the ''footprint'' of the NKIR on the alpha 1 helix of the class I MHC molecule HLA-C and its associated beta strands are similar in position to the site occupied by superantigens on and behind the alpha 1 helix of the class II MHC molecule HLA-DR1, but further toward its C-terminus. The intermediate affinity binding of NKIR to HLA-C, determined by alpha 73 and alpha 90, has an essential role in preventing cross-reactivity and ensuring the availability of NK cells for immunosurveillance; low affinity and high affinity mutants are both physiologically impaired.