Human melanoma cell secreting human leukocyte antigen-G5 inhibit natural killer cell cytotoxicity by impairing lytic granules polarization toward target cell.
Human leukocyte antigen-G (HLA-G) is a nonclassical tolerogenic molecule that can be expressed either as membrane bound (HLA-G1) or secreted (HLA-G5) isoforms. Upregulation of HLA-G1 or HLA-G5 expression by tumor cells constitutes an efficient way to escape from antitumoral immune responses. The inhibitory role of HLA-G1 on NK cell cytotoxicity is well characterized; however, that of the HLA-G5 isoform secreted by tumor is poorly understood. Our results indicate that the HLA-G5 isoform secreted by M8 melanoma cells is able to protect them from natural killer leukemia cell line (NKL) cytotoxicity. Analysis of NKL/M8-HLA-G5 conjugates by confocal microscopy demonstrates that the inhibition of NKL cytotoxic activity resulted from an impairment of NKL actin reorganization and perforin granules polarization toward M8-HLA-G5 target cell. This study also indicates that HLA-G5 soluble isoform remains evenly distributed in the cytoplasm of M8-HLA-G5 conjugated to NKL cells, suggesting that HLA-G5 does not require to polarize toward effector cell to induce efficient inhibition. These results highlight the inhibitory mechanisms mediated through HLA-G5 leading to tumor escape from NK cell cytotoxicity.
Lesport
Emilie
E
Commissariat à l'Energie Atomique, I2BM Service de Recherches en Hemato-Immunologie, Institut Universitaire d'Hematologie, Hôpital Saint Louis, Paris, France.
Baudhuin
Jeremy
J
LeMaoult
Joel
J
Sousa
Sylvie
S
Doliger
Christelle
C
Carosella
Edgardo D
ED
Favier
Benoit
B
D000199:Actins / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D019139:Tumor Escape
D000199:Actins; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D054353:Perforin