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-restricted, new evidence suggests that NK activity can be either up- or down-regulated after interaction with the peptide-MHC-class-I complex expressed on target cells. However, the epitope(s) recognized by NK cells have remained ill-defined. We investigated NK cell recognition of synthetic peptides representing a portion of a self-protein encoded by the HER-2/neu (HER-2) proto-oncogene and presented by HLA-A2. HER-2 nonapeptides C85, E89, and E75 were found partially to protect T2 targets from lysis by freshly isolated and interleukin-2(IL-2)-activated NK cells (either HLA-A2(+) or A2(-)). This inhibition was not solely due to changes in the level of HLA-A2 expression or conformation of serological HLA-A2 epitopes. Using single-amino-acid variants 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 suggest similarities in the mechanism of target recognition by NK and T cells. This information may be important for understanding the mechanisms of tumor escape from immunosurveillance and could help explain the aggressiveness of HER-2-overexpressing tumor cells.
Anderson
L D
LD
The University of Texas M.D. Anderson Cancer Center, Department of Gynecologic Oncology, Box 67, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
Hudson
J M
JM
Savary
C A
CA
Fisk
B
B
Gershenson
D M
DM
Ioannides
C G
CG
D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D014162:Transfection
D000939:Epitopes; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715470:MAS1 protein, human