Immunotherapeutic potential for ceramide-based activators of iNKT cells

Invariant natural killer T (iNKT) cells are a subpopulation of T cells that are reactive with glycolipids that are bound by CD1d antigen-presenting molecules. alpha-Galactosylceramide (alpha-GalCer) is a synthetic glycolipid that is a potential treatment for several autoimmune diseases, infectious diseases and cancer. Its therapeutic effect can be traced back to its ability to bind CD1d and activate iNKT cells, which results in the production of T helper I (Th1) and Th2 cytokines. However, the effectiveness of alpha-GalCer therapy is limited by the opposing actions of Th1 and Th2 cytokines. The alpha-GalCer analogs OCH and the recently designed and synthesized C-glycosidic alpha-GalCer selectively activate one of two types of cytokine profiles, possibly because either reduced or enhanced overall stability of the CD1d-glycolipid-T-cell-receptor complex leads to a higher potency in vivo, compared with the parent compound. These discoveries boost the potential of glycolipid-based therapies.