The alpha1 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 HLA class 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 structure similar to that of classical HLA class I antigens. The HLA-G2 protein, deduced from an alternatively spliced transcript, consists of the alpha1 domain linked to the alpha3 domain. In this study we demonstrate that (i) HLA-G2 is present at the cell surface as a truncated class I molecule associated with beta2-microglobulin; (ii) NK cytolysis, observed in peripheral blood mononuclear cells and in polyclonal CD3(-) CD16(+) CD56(+) NK cells obtained from 20 donors, is inhibited by both HLA-G1 and HLA-G2; this HLA-G-mediated inhibition is reversed by blocking HLA-G with a specific mAb; this led us to the conjecture that HLA-G is the public ligand for NK inhibitory receptors (NKIR) present in all individuals; (iii) the alpha1 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 lysis by the T cell leukemia NK-like YT2C2 clone due to interaction between the HLA-G isoform on the target cell surface and a membrane receptor on YT2C2. Because NKIR1 and NKIR2, known to interact with HLA-G, were undetectable on YT2C2, we conclude that a yet-unknown specific receptor for HLA-G1 and HLA-G2 is present on these cells.
Rouas-Freiss
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N
Service de Recherches en Hémato-Immunologie, Commissariat à l'Energie Atomique-Departement Recherche Medicale, Direction des Sciences du Vivant, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cédex 10, France.
Marchal
R E
RE
Kirszenbaum
M
M
Dausset
J
J
Carosella
E D
ED
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002462:Cell Membrane / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005091:Exons; D005434:Flow Cytometry; D005822:Genetic Vectors; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D004915:Leukemia, Erythroblastic, Acute; D008214:Lymphocytes / Q000276:immunology; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D015183:Restriction Mapping; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000276:immunology
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin