Abstract

Abstract NKT cells with an invariant TCR (iNKT cells) represent a unique subset of T lymphocytes sharing properties of both natural killer cells and T lymphocytes. iNKT cells regulate immune responses by rapidly secreting large amount of cytokines. Their development and maturation is dependent on self-Ags presented by CD1d, a MHC class I-like antigen-presenting molecule. It is widely believed that these self-Ags are glycosphingolipids. Here, we used LY-B, a sphingolipid-deficient cell line, to study the nature of the endogenous lipid Ags that stimulate iNKT cells. With only 10% glycosphingolipid level of wild type cells, and these predominantly ganglioside GM3, mouse CD1d transfectants of LY-B still showed comparable ability to stimulate iNKT cell hybridomas. The self-Ag presentation was CD1d-dependent, because a specific antibody against mouse CD1d could block it. The finding was further confirmed by a cell-free Ag presentation assay. Surprisingly, alkaline digestion, which specifically hydrolyzes acyl fatty acids from phospholipids, dramatically reduced the antigenic activity of a cell sonicate while αGalCer was not affected. Sphingolipid ceramide N-deacylase, which specifically frees acyl fatty acids from sphingolipids, eliminated the activity of αGalCer without any effect on the activity in the cell sonicate. These data show that the endogenous Ags stimulating iNKT cells need not be glycosphingolipids.

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