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¹ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
² Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
³ La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

Address correspondence to Paul B. Chapman, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: 212-639-5015; Fax: 212-794-4352; E-mail: chapmanp{at}mskcc.org

GD3, a ganglioside expressed on human melanoma, can be recognized by the humoral immune system. In this paper, we demonstrate that immunizing mice with the human melanoma cell line SK-MEL-28 (GD3⁺ GM2^- CD1^-) or with syngeneic APCs loaded with GD3 can induce a GD3-reactive natural killer T (NKT) cell response. GD3-reactive NKT cells were detected among splenocytes of immunized mice at frequencies of 1:2,000 both by ELISPOT and GD3-loaded mouse CD1d tetramer analysis. GD3-reactive NKT cells did not react with GM2, a closely related ganglioside, and were not detectable in unimmunized mice. GD3-reactive NKT cells initially produced IL-4 and IFN- followed by IL-10. They were CD1d restricted in that reactivity was abrogated when APCs were blocked with anti-CD1d monoclonal antibody before being loaded with GD3 or when APCs from CD1d knockout mice were used. Because SK-MEL-28 does not express any isoform of human CD1, GD3 must be cross-presented by murine APCs in vivo. This is the first analysis of a natural ligand for mouse NKT cells and the first definitive paper of cross-presentation to NKT cells. This could be a mechanism for NKT cell recognition of tumor gangliosides in CD1^- tumors.

Key Words: NKT cell • -galactosylceramide • CD1d • tetramer • melanoma

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