Chemical Glycobiology of Glycosphingolipids

The MHC-I like CD1d presents glycolipids to NKT cells, a subpopular T cells, for recognition while the classic MHC molecules present peptides to regulatory T cells. Upon stimulation, NKT cells produce cytokines and chemokines to regulate autoimmune responses. The marine sponge α-galactosylceramides, bacterial α-galacturonosylceramides and mammalian isoglobotrihexosylceramide are the well-known glycolipids which can be presented by CD1d to NKT cells. The former two have similar structures with an α-linkage between the sugar part and ceramide part, while the latter possesses a β-linkage. Structure activity relationship studies of the glycolipids were employed to demonstrate the interactions among CD1d, glycolipid and the T cell receptor (TCR) of NKT cells. Functionalization on the C3′ and C4′ of the KRN7000 showed that these analogues could selectively bind different species of NKT cells. By variation of the ceramide of iGb3, the HO-iGb3 which has phytosphingosine as the lipid part, was shown to possess greater potential in stimulating NKT cells to release cytokines. Four deoxy-iGb3 analogues of the terminal sugar were also prepared to illustrate the role of these hydroxy groups in communicating with NKT cells. A metabolically stable iGb3 analogue, named S -iGb3, was synthesized to test whether it can improve activity.