New Paradigm in NKT Cell Antigens: MCS‐0208 (2‐(Hydroxymethyl)phenylthio‐phytoceramide) – an Aryl‐Phytoceramide Compound with a Single Hydroxyl Group Stimulates NKT Cells

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.

Chemical Biology of αGalCer: A Chemist's Toolbox for the Stimulation of Invariant Natural Killer T (iNKT) Cells

“…We expect that this, combined with immunological investigations proving their utility and advances in chemical synthesis, will underpin future studies that can pave the way for clinical use of compounds exploiting this biological mechanism. Here, we have described studies centered on αGalCer, however there is a future beyond galactose, as evident by studies of e. g. βManCer [167] and even non‐glycosylated lipids [168] …”

“…Here, we have described studies centered on αGalCer, however there is a future beyond galactose, as evident by studies of e. g. βManCer [167] and even non-glycosylated lipids. [168]…”