HER-2/neu peptide specificity in the recognition of HLA-A2 by natural killer cells

Although natural killer (NK) cells have been described as non-MHC-restricte d, new evidence suggests that NK activity can be either up- or down-regulat ed after interaction with the peptide-MHC-class-I complex expressed on targ et cells. However, the epitope(s) recognized by NK cells have remained ill- defined. We investigated NK cell recognition of synthetic peptides represen ting a portion of a self-protein encoded by the HER-2/neu (HER-2) proto-onc ogene and presented by HLA-A2. HER-2 nonapeptides C85, E89, and E75 were fo und partially to protect T2 targets from lysis by freshly isolated and inte rleukin-2 (IL-2) -activated NK cells (either HLA-A2(+) or A2(-)). This inhi bition was not solely due to changes in the level of HLA-A2 expression or c onformation of serological HLA-A2 epitopes. Using single-amino-acid variant s at position 1 (P1) of two HER-2 peptides, we observed that protection of targets was dependent on the sequence and the side-chain. These results sug gest similarities in the mechanism of target recognition by NK and T cells. This information may be important for understanding the mechanisms of tumo r escape from immunosurveillance and could help explain the aggressiveness of HER-2-overexpressing tumor cells.