The
glycosphingolipid isoglobotrihexosylceramide, or isogloboside 3 (iGb3), is believed to be critical for
natural killer T (NKT) cell development and
self-recognition in
mice and humans. Furthermore, iGb3 may represent an important obstacle in
xenotransplantation, in which this
lipid represents the only other form of the major xenoepitope Galalpha(1,3)Gal. The role of iGb3 in
NKT cell development is controversial, particularly with one study that suggested that
NKT cell development is normal in
mice that were rendered deficient for the
enzyme iGb3
synthase (iGb3S). We demonstrate that spliced iGb3S
mRNA was not detected after extensive analysis of
human tissues, and furthermore, the iGb3S gene contains several
mutations that render this product nonfunctional. We directly tested the potential functional activity of human iGb3S by expressing chimeric molecules containing the
catalytic domain of human iGb3S. These hybrid molecules were unable to
synthesize iGb3, due to at least one
amino acid substitution. We also demonstrate that purified normal human anti-Gal
immunoglobulin G can bind iGb3
lipid and mediate complement
lysis of transfected
human cells expressing iGb3. Collectively, our data suggest that iGb3S is not expressed in humans, and even if it were expressed, this
enzyme would be inactive. Consequently, iGb3 is unlikely to represent a primary natural ligand for
NKT cells in humans. Furthermore, the absence of iGb3 in humans implies that it is another source of foreign Galalpha(1,3)Gal xenoantigen, with obvious significance in the field of
xenotransplantation.
