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...

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Autores principales:	Dale Christiansen, Julie Milland, Effie Mouhtouris, Hilary Vaughan, Daniel G Pellicci, Malcolm J McConville, Dale I Godfrey, Mauro S Sandrin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/794d25e6ecf345018b25228c5316ba1d
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spelling	oai:doaj.org-article:794d25e6ecf345018b25228c5316ba1d2021-11-25T05:33:17ZHumans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation.1544-91731545-788510.1371/journal.pbio.0060172https://doaj.org/article/794d25e6ecf345018b25228c5316ba1d2008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18630988/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The 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.Dale ChristiansenJulie MillandEffie MouhtourisHilary VaughanDaniel G PellicciMalcolm J McConvilleDale I GodfreyMauro S SandrinPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 6, Iss 7, p e172 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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.
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.
format	article
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
title	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_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_sort	humans lack igb3 due to the absence of functional igb3-synthase: implications for nkt cell development and transplantation.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/794d25e6ecf345018b25228c5316ba1d
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Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation.

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