NK cell recognition of MHC class I: NK cells are sensitive to peptide-binding groove and surface α-helical mutations that affect T cells

NK cells directly or indirectly recognize MHC class I molecules, but the exact structures recognized remain poorly defined. We address the hypothesis that NK cells, like T cells, directly contact peptide/MHC class I complexes. This hypothesis predicts that NK-mediated killing is inhibited by amino acid substitutions in the MHC class I peptide-binding groove and in solvent-accessible α-helical residues proposed to contact the TCR. In our model system, target cell HLA-B*0702 inhibited killing by unstimulated peripheral blood NK cells. NK-mediated killing was increased significantly by 6 of 11 peptide-binding groove mutations and 6 of 12 TCR contact site mutations, but only 1 of 6 mutations outside these sites. Many of the mutations that inhibited NK-mediated killing prohibited killing by 12 alloreactive CTL clones. These data suggest that NK receptors directly contact HLA-B*0702, focusing on the peptide-binding groove and surrounding α-helices. NK cell lines exhibited multiple HLA recognition patterns, which is consistent with nonuniform expression of MHC receptors by NK cells. We propose that NK cells, like αβ T cells and some anti-MHC Abs, directly or indirectly recognize MHC-bound peptides.