Peptides isolated from HLA-Cw*0304 confer different degrees of protection from natural killer cell-mediated lysis.
HLA class I molecules bind peptides derived from proteins degraded in the cytoplasm and display them for surveillance by the immune system. The recognition of HLA class I molecules by natural killer (NK) cells generally inhibits the lytic process. To investigate the role of peptides in the interaction between HLA class I molecules and NK receptors, we first had to identify representative endogenous peptides. Individual peptides bound to HLA-Cw*0304 were isolated and sequenced by tandem mass spectrometry. These peptides ranged in length from 8 to 11 residues and shared an alanine at position 2 and a C-terminal leucine. The murine transporters associated with antigen processing (TAP)-deficient cell line RMA-S was transfected with HLA-Cw*0304 to test whether HLA molecules loaded with a single peptide could deliver the inhibitory signal to NK cells expressing p58.2, which is a killer cell inhibitory receptor known to interact with HLA molecules bearing the HLA-Cw3 public epitope. We found that, in the absence of exogenous peptides, the HLA-Cw*0304 transfectants were killed at levels comparable to untransfected RMA-S cells whereas protection from lysis required both HLA-Cw*0304 heavy chain expression and an exogenously added HLA-Cw*0304-binding peptide. Importantly, not only were HLA-Cw*0304-binding peptides required for protection, but the ability of individual peptides to provide protection differed widely. These studies indicate that the ability to distinguish between subsets of peptides may be a general feature of HLA class I recognition by NK cells.
Zappacosta
F
F
Laboratory of Molecular Structure, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852, USA.
Borrego
F
F
Brooks
A G
AG
Parker
K C
KC
Coligan
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D000939:Epitopes / Q000276:immunology; D015236:HLA-C Antigens / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection
D000939:Epitopes; D015236:HLA-C Antigens; C106548:HLA-C*03:04 antigen; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011994:Recombinant Proteins