THE ALPHA(1) DOMAIN OF HLA-G1 AND HLA-G2 INHIBITS CYTOTOXICITY INDUCED BY NATURAL-KILLER-CELLS - IS HLA-G THE PUBLIC LIGAND FOR NATURAL-KILLER-CELL INHIBITORY RECEPTORS

We have investigated the protective role of the membrane-bound HLA-G1 and HLA-G2 isoforms against natural killer (NK) cell cytotoxicity. For this purpose, HLA-G1 and HLA-G2 cDNAs were transfected into the BLA c lass I-negative human K562 cell line, a known reference target for NK lysis. The HLA-G1 protein, encoded by a full-length mRNA, presents a s tructure similar to that of classical HLA class I antigens. The HLA-G2 protein, deduced from an alternatively spliced transcript, consists o f the alpha(1) domain linked to the alpha(3) domain. In this study we demonstrate that (i) HLA-G2 is present at the cell surface as a trunca ted class I molecule associated with beta(2)-microglobulin; (ii) NK cy tolysis, observed in peripheral blood mononuclear cells and in polyclo nal CD3(-) CD16(+) CD56(+) NK cells obtained from 20 donors, is inhibi ted by both HLA-G1 and HLA-G2; this HLA-G-mediated inhibition is rever sed by blocking HLA-G with a specific mAb; this led us to the conjectu re that HLA-G is the public ligand for NK inhibitory receptors (NMR) p resent in all individuals; (iii) the alpha(1) domain common to HLA-G1 and HLA-G2 could mediate this protection from NK lysis; and (iv) when transfected into the K562 cell line, both HLA-G1 and HLA-G2 abolish ly sis by the T cell leukemia NK-like YT2C2 clone due to interaction betw een the HLA-G2 isoform on the target cell surface and a membrane recep tor on YT2C2. Because NKIR1 and NKIR2, known to interact with HLA-G, w ere undetectable on YT2C2, we conclude that a yet-unknown specific rec eptor for HLA-G1 and HLA-G2 is present on these cells.