<p>Invariant
natural killer T cells (iNKT), a subclass of white blood cells, are responsible
for the production of pro-inflammatory cytokines which induce a systemic immune
response. They are distinctive in having an invariant T-cell receptor that
recognizes glycolipid antigens presented by the class I major histocompatibility
complex-related protein CD1d, which is conserved across multiple mammalian
species in a class of proteins well-renowned for their high degree of
polymorphism. This receptor’s first identified antigen is the potent KRN7000, a
glycosphingolipid isolated from bacteria that were found on a Japanese marine
sponge. The corresponding terrestrial antigen remained unidentified until quite
recently, when diacylglycerol-containing glycolipids, reported to activate iNKT
cells, were isolated from <i>Streptococcus pneumoniae</i>. We report the total
synthesis and immunological re-evaluation of these two glycolipids. The
compounds are unable to activate iNKT cells. Computational modelling shows that
these ligands, while being capable of interacting with the CD1d receptor,
create a different surface for the binary complex that makes formation of the
ternary complex with the iNKT T-cell receptor difficult. Together these results
suggest that the reported activity might have been due to an impurity in the
original isolated sample, and highlights the importance of taking care when
reporting biological activity from isolated natural products.<b></b></p>
The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation
