Understanding NKT cells through sulfatide analogues

Abstract The goal of this research is to further investigate NKT cell activation using sulfatide analogues. NKT cells have been shown to play a significant role in mediating inflammatory immune responses and because of this, there has been strong interest in pharmacologically regulating this compartment to fight cancer. NKT cells recognize lipids that are loaded on CD1d molecules on the surface of cells, and it has been shown that structural modifications of these lipids directly affect NKT cell activation and polarization. Our work is focused on the impact of modifications of sulfatide, which is a glycolipid that can be loaded onto CD1d which is known to activate sulfatide-reactive (generally type II) NKT cells when presented by CD1d monomers on plastic. We have numerous sulfatide analogues with modifications (based on previous work with alpha-galactosylceramide analogues) on the acyl chain, sphingosine chain, and changes of beta-anomeric to alpha-anomeric. These analogues have been screened with NKT cell hybridomas, DN32 and XV19, to assess their effect on activation of type I and type II NKT cells, respectively. We observed that alterations in the sphingosine or acyl chain in sulfatides do not always mimic the effects on activity of similar changes in alpha-galactosylceramide analogues and that numerous sulfatide analogues can activate DN32 (not sulfatide-reactive) when presented on CD1d monomer or bone marrow-derived dendritic cells. Our results provide further insight into NKT cell activation and have identified sulfatide analogues that may be applicable to cancer therapy by activating type I NKT cells. NCI, NIH intramural research program (NIA-C-004020), and institutional grants of NIH (R01 GM111849)