Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and -independent mechanisms.
Siglec-7 is a sialic acid binding receptor with inhibitory potential, expressed on human NK cells and monocytes. It has an unusual binding preference for alpha2,8-linked disialic acids, such as those displayed by ganglioside GD3. Here we have investigated whether siglec-7-GD3 interactions are able to modulate NK cell cytotoxicity. Using synthetic polyacrylamide glycoprobes, siglec-7 was found to be masked at the NK cell surface but it could be unmasked by sialidase treatment of NK cells. GD3 synthase-transfected P815 target cells expressed high levels of GD3 and bound strongly to recombinant siglec-7-Fc protein. Surprisingly, GD3 synthase-transfected P815 cells were killed more effectively by untreated cells in a siglec-7-independent manner. However, following sialidase treatment of NK cells, a siglec-7-dependent inhibition of killing was observed. These findings have important implications for NK cell cytotoxicity against tumor cells like melanoma that express high levels of GD3 ganglioside.
Nicoll
Gavin
G
The School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, GB.
Avril
Tony
T
Lock
Kevin
K
Furukawa
Koichi
K
Bovin
Nicolai
N
Crocker
Paul R
PR
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000502:physiology*; D001665:Binding Sites; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004187:Disaccharides / Q000378:metabolism; D005732:Gangliosides / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D037102:Lectins / Q000737:chemistry / Q000502:physiology*; D034801:Mastocytoma / Q000473:pathology; D051379:Mice; D009439:Neuraminidase / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000276:immunology; D019139:Tumor Escape
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004187:Disaccharides; D005732:Gangliosides; D037102:Lectins; D011993:Recombinant Fusion Proteins; C402206:SIGLEC7 protein, human; D012794:Sialic Acids; C026226:ganglioside, GD3; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D009439:Neuraminidase