Sphingolipidoses are rare genetic diseases caused mainly by defective activity of lysosomal hydrolases, which leads to accumulation of undegraded glycosphingolipids. Numerical and functional defects of iNKT cells have been described in sphingolipidoses including Fabry disease (accumulation of globotriaosylceramide, Gb3).

Little is known whether the accumulation of CD1d-binding and non-stimulatory glycosphingolipids interfere with iNKT cell activation.

We found that Gb3 can negatively modulate iNKT cell activation by competing with endogenous and exogenous lipid antigens for CD1d binding. Monocytes or immobilized CD1d incubated simultaneously with Gb3 and α-Galactosylceramide (α-GalCer) induced a weaker iNKT cell response as compared to incubation with α-GalCer alone. This effect was also applicable to endogenous antigens, as loading of antigen-presenting cells with Gb3 reduced iNKT cell autoreactivity. We confirmed that Gb3 was competing with α-GalCer for CD1d binding by finding a reduction in the formation of CD1d:α-GalCer complexes in the presence of Gb3. This competition effect was also observed in vivo when iNKT cells were stimulated by dendritic cells loaded with both Gb3 and α-GalCer.

The analysis of iNKT cells on sphingolipidoses highlights the complexity of iNKT cell activation and the importance of non-antigenic glycosphingolipids in the modulation of this process.