PEPTIDES ISOLATED FROM HLA-CW-ASTERISK-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 pepti des in the interaction between HLA class I molecules and NK receptors, we first had to identify representative endogenous peptides, Individu al peptides bound to HLA-Cw0304 were isolated and sequenced by tandem mass spectrometry, These peptides ranged in length from 8 to 11 resid ues 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-Cw0304 to test whether HLA molecules loaded with a single peptide could deliver the inhibitory si gnal to NK cells expressing p58.2, which is a killer cell inhibitory r eceptor known to interact with HLA molecules bearing the HLA-Cw3 publi c epitope, We found that, in the absence of exogenous peptides, the HL A-Cw0304 transfectants were killed at levels comparable to untransfec ted RMA-S cells whereas protection from lysis required both HLA-Cw030 4 heavy chain expression and an exogenously added HLA Cw0304-binding peptide. Importantly, not only were HLA-Cw0304-binding peptides requi red 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 H LA class I recognition by NK cells.