Invariant natural killer T (iNKT) cells are an attractive therapeutic target in
autoimmune diseases, since they play a major role in immune regulation. iNKT cells recognize
glycolipid antigens presented by CD1d molecules that resemble the non-polymorphic MHC class I
protein.
alpha-galactosylceramide (
alpha-GalCer) isolated from marine sponge has long been used as a prototype iNKT cell
ligand in the laboratory. As
alpha-GalCer is the most efficacious
ligand for iNKT cells, its potential to treat
autoimmune disease has been evaluated in animal models. Previous studies showed that
alpha-GalCer effectively suppressed disease in some autoimmunity models, but not in others. This inconsistency may be attributed to the ability of
alpha-GalCer to induce the production of both proinflammatory Th1 and anti-inflammatory Th2
cytokines by iNKT cells. To overcome this issue, we and other groups have synthesized new, unnatural
glycolipids by modifying the structure of
alpha-GalCer. These efforts have led to an identification of
glycolipid compounds that provoke the production of Th2 (but not Th1)
cytokines by iNKT cells. Among these novel
ligands, an
alpha-GalCer analogue named OCH, which contains a truncated
sphingosine chain, induces a Th2 biased response by murine iNKT cells. Here we describe that OCH also polarizes human iNKT cells towards Th2, which opens up a new avenue for the clinical application of
glycolipid compounds in treating of
autoimmune diseases such as
multiple sclerosis. The pursuit of synthetic
glycolipid antigens has the great potential to lead to a better understanding of the regulatory effects of human iNKT cells and development of a new therapeutic agent for
autoimmune diseases.