Fine specificity of NKT cells against GD3 ganglioside and identification of GM3 as an inhibitory NKT cell ligand Free

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GD3, a ganglioside expressed on melanoma, is the only tumor-associated glycolipid described so far that can induce a CD1d-restricted NKT cell response. We analyzed the fine specificity of GD3-reactive NKT cells and discovered that immunization with GD3 induced two populations of GD3-reactive NKT cells. One population was CD4⁺CD8^- and was specific for GD3; the other population was CD4^-CD8^- and cross-reacted with GM3 in a CD1d-restricted manner. GD3-reactive NKT cells did not cross-react with GM2, GD2 or lactosylceramide indicating the T-cell receptors that react with GD3 recognize glucose-galactose linked to at least one N-acetyl-neuraminic acid but will not accommodate a terminal N-acetylgalactosamine. Immunization with GM2, GM3, GD2, or lactosylceramide did not induce an IL-4 or IFN-γ NKT cell response against these glycolipids. Co-immunization or GM3-loaded with GD3-loaded APCs suppressed the NKT cell response to GD3 in a CD1d-restricted manner. This suppressive effect was specific for GM3 and was a local effect lasting 2-4 days. In vitro, GM3-loaded APCs also suppressed the IL-4 response of NKT cells to αGalCer. GM3 is the first inhibitory NKT cell ligand to inhibit an in vivo NKT cell response.