Abstract
Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS‐0208, an unprecedented arylthioether‐phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α‐galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’‐OH and 3’‐OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.
Highlights
Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein
There is a general agreement on the critical importance of 2’-OH and 3’-OH for CD1d recognition while the modification on other parts of the galactose can be somehow modified to modulate the interaction with the T cell receptor (TCR) and, as a result, modulate the NKT cell response
We have presented a new NKT cell recognized antigen, Medicinal Chemistry and Synthesis (MCS)-0208 (13), with an unprecedented structure having an ortho-hydroxymethyl substituted phenylthioether as a sugar mimetic in the glycolipid. These results open the possibility of further development for new families of compounds capable to stimulate NKT cells
Summary
Candidate[15] at the time of this work was started it was refused.[16,17]. At 10ng/mL our compound showed similar IFN-γ levels than aGalCer significant lower levels of IL-4 were detected, pointing to a marked Th1 biased response These results were unexpected considering the low functionalization of the aromatic ring and the low number of potential contacts of the antigen with the contact surface of CD1d and TCR proteins. A correlation between H-Bond interaction and the binding affinity together with the potency of NKT cells activation is an attractive hypothesis which is beyond the scope of this preliminary study As it could be expected, the number of interactions mediated by “head” group of new thioaryl-ceramide ligand MCS-0208 (13) decreased due to low level of functionality compared to the aminocyclitol scaffold. More extensive structure-activity studies could put some light on this new family potential and deeper structural are needed to corroborate the above mentioned structural hypothesis
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