Humans lack iGb3 due to the absence of functional iGb3-synthase: Implications for NKT cell development and transplantation

被引:86
作者
Christiansen, Dale [1 ]
Milland, Julie [1 ]
Mouhtouris, Effie [1 ]
Vaughan, Hilary [1 ]
Pellicci, Daniel G. [2 ]
McConville, Malcolm J. [3 ]
Godfrey, Dale I. [2 ]
Sandrin, Mauro S. [1 ]
机构
[1] Univ Melbourne, Dept Surg, Austin Hlth No Hlth, Heidelberg, Vic, Australia
[2] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia
[3] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic, Australia
来源
PLOS BIOLOGY | 2008年 / 6卷 / 07期
关键词
D O I
10.1371/journal.pbio.0060172
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Gala(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 Gala(1,3) Gal xenoantigen, with obvious significance in the field of xenotransplantation.
引用
收藏
页码:1527 / 1538
页数:12
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