Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation.
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-07-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18630988/pdf/?tool=EBI |
| _version_ | 1818931861151285248 |
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| author | Dale Christiansen Julie Milland Effie Mouhtouris Hilary Vaughan Daniel G Pellicci Malcolm J McConville Dale I Godfrey Mauro S Sandrin |
| author_facet | Dale Christiansen Julie Milland Effie Mouhtouris Hilary Vaughan Daniel G Pellicci Malcolm J McConville Dale I Godfrey Mauro S Sandrin |
| author_sort | Dale Christiansen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T04:23:19Z |
| format | Article |
| id | doaj.art-794d25e6ecf345018b25228c5316ba1d |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-20T04:23:19Z |
| publishDate | 2008-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-794d25e6ecf345018b25228c5316ba1d2022-12-21T19:53:35ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852008-07-0167e17210.1371/journal.pbio.0060172Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation.Dale ChristiansenJulie MillandEffie MouhtourisHilary VaughanDaniel G PellicciMalcolm J McConvilleDale I GodfreyMauro S SandrinThe 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18630988/pdf/?tool=EBI |
| spellingShingle | Dale Christiansen Julie Milland Effie Mouhtouris Hilary Vaughan Daniel G Pellicci Malcolm J McConville Dale I Godfrey Mauro S Sandrin Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. PLoS Biology |
| title | Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. |
| title_full | Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. |
| title_fullStr | Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. |
| title_full_unstemmed | Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. |
| title_short | Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. |
| title_sort | humans lack igb3 due to the absence of functional igb3 synthase implications for nkt cell development and transplantation |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18630988/pdf/?tool=EBI |
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