Identification of endogenous antigens that regulate natural killer T (NKT) cell development and function is a major goal in immunology.

Originally the glycosphingolipid, iGb3, was suggested to be the main endogenous ligand in both mice and humans. However, recent studies have challenged this hypothesis. From a xenotransplantation (animal to human transplants) perspective, iGb3 expression is also important as it represents another form of the major xenoantigen Gala(1,3)Gal. In this week's issue of PLoS Biology, Mauro Sandrin and colleagues assess whether humans express a functional iGb3 synthase (iGb3S), the enzyme responsible for lipid synthesis.

The authors showed that spliced iGb3S mRNA was not detected in any human tissue analysed. Furthermore, chimeric molecules composed of the catalytic domain of human iGb3S were unable to synthesize iGb3 lipid, due to at least one amino acid substitution.

They also demonstrated that purified human anti-Gal antibodies bound iGb3 lipid and mediated destruction of cells transfected to express iGb3. A nonfunctional iGb3S in humans has two major consequences: (1) iGb3 is unlikely to be a natural human NKT ligand and (2) natural human anti-Gal antibodies in human serum could react with iGb3 on the surface of organs from pigs, marking these tissues for immunological destruction.

Christiansen D, Milland J, Mouhtouris E, Vaughan H, Pellicci DG, et al. (2008)
" Humans lack iGb3 due to the absence of functional iGb3-synthase: Implications for NKT cell development and transplantation."
PLoS Biol 6(7): e172. doi:10.1371/journal.pbio.0060172
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