Immunologic glycosphingolipidomics and NKT cell development in mouse thymus

Yunsen Li; Prakash Thapa; David Hawke; Yuji Kondo; Keiko Furukawa; Koichi Furukawa; Fong-Fu Hsu; Dietlind Adlercreutz; Joel Weadge; Monica M Palcic; Peng G Wang; Steven B Levery; Dapeng Zhou

doi:10.1021/pr801040h

Immunologic glycosphingolipidomics and NKT cell development in mouse thymus

Yunsen Li, Prakash Thapa, David Hawke, Yuji Kondo, Keiko Furukawa, Koichi Furukawa, Fong-Fu Hsu, Dietlind Adlercreutz, Joel Weadge, Monica M Palcic, Peng G Wang, Steven B Levery, Dapeng Zhou

Glycomics Program

39 Citations (Scopus)

Abstract

Invariant NKT cells are a hybrid cell type of Natural Killer cells and T cells, whose development is dependent on thymic positive selection mediated by double positive thymocytes through their recognition of natural ligands presented by CD1d, a nonpolymorphic, non-MHC, MHC-like antigen presenting molecule. Genetic evidence suggested that beta-glucosylceramide derived glycosphingolipids (GSLs) are natural ligands for NKT cells. N-butyldeoxygalactonojirimycin (NB-DGJ), a drug that specifically inhibits the glucosylceramide synthase, inhibits the endogenous ligands for NKT cells. Furthermore, we and others have found a beta-linked glycosphingolipid, isoglobotriaosylceramide (iGb3), is a stimulatory NKT ligand. The iGb3 synthase knockout mice have a normal NKT development and function, indicating that other ligands exist and remain to be identified. In this study, we have performed a glycosphingolipidomics study of mouse thymus, and studied mice mutants which are deficient in beta-hexosaminidase b or alpha-galactosidase A, two glycosidases that are up- and downstream agents of iGb3 turnover, respectively. Our mass spectrometry methods generated a first database for glycosphingolipids expressed in mouse thymus, which are specifically regulated by rate-limiting glycosidases. Among the identified thymic glycosphingolipids, only iGb3 is a stimulatory ligand for NKT cells, suggesting that large-scale fractionation, enrichment and characterization of minor species of glycosphingolipids are necessary for identifying additional ligands for NKT cells. Our results also provide early insights into cellular lipidomics studies, with a specific focus on the important immunological functions of glycosphingolipids.

Original language	English
Journal	Journal of Proteome Research
Volume	8
Issue number	6
Pages (from-to)	2740-51
Number of pages	11
ISSN	1535-3893
DOIs	https://doi.org/10.1021/pr801040h
Publication status	Published - 2009

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10.1021/pr801040h

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@article{df9dac7094b811df928f000ea68e967b,

title = "Immunologic glycosphingolipidomics and NKT cell development in mouse thymus",

abstract = "Invariant NKT cells are a hybrid cell type of Natural Killer cells and T cells, whose development is dependent on thymic positive selection mediated by double positive thymocytes through their recognition of natural ligands presented by CD1d, a nonpolymorphic, non-MHC, MHC-like antigen presenting molecule. Genetic evidence suggested that beta-glucosylceramide derived glycosphingolipids (GSLs) are natural ligands for NKT cells. N-butyldeoxygalactonojirimycin (NB-DGJ), a drug that specifically inhibits the glucosylceramide synthase, inhibits the endogenous ligands for NKT cells. Furthermore, we and others have found a beta-linked glycosphingolipid, isoglobotriaosylceramide (iGb3), is a stimulatory NKT ligand. The iGb3 synthase knockout mice have a normal NKT development and function, indicating that other ligands exist and remain to be identified. In this study, we have performed a glycosphingolipidomics study of mouse thymus, and studied mice mutants which are deficient in beta-hexosaminidase b or alpha-galactosidase A, two glycosidases that are up- and downstream agents of iGb3 turnover, respectively. Our mass spectrometry methods generated a first database for glycosphingolipids expressed in mouse thymus, which are specifically regulated by rate-limiting glycosidases. Among the identified thymic glycosphingolipids, only iGb3 is a stimulatory ligand for NKT cells, suggesting that large-scale fractionation, enrichment and characterization of minor species of glycosphingolipids are necessary for identifying additional ligands for NKT cells. Our results also provide early insights into cellular lipidomics studies, with a specific focus on the important immunological functions of glycosphingolipids.",

author = "Yunsen Li and Prakash Thapa and David Hawke and Yuji Kondo and Keiko Furukawa and Koichi Furukawa and Fong-Fu Hsu and Dietlind Adlercreutz and Joel Weadge and Palcic, {Monica M} and Wang, {Peng G} and Levery, {Steven B} and Dapeng Zhou",

note = "Keywords: Animals; Galactosyltransferases; Gene Expression; Genomics; Globosides; Glycosphingolipids; Hydrogen-Ion Concentration; Ligands; Mice; Mice, Knockout; Natural Killer T-Cells; Thymus Gland; alpha-Galactosidase; beta-Hexosaminidase beta Chain",

year = "2009",

doi = "10.1021/pr801040h",

language = "English",

volume = "8",

pages = "2740--51",

journal = "Journal of Proteome Research",

issn = "1535-3893",

publisher = "American Chemical Society",

number = "6",

}

TY - JOUR

T1 - Immunologic glycosphingolipidomics and NKT cell development in mouse thymus

AU - Li, Yunsen

AU - Thapa, Prakash

AU - Hawke, David

AU - Kondo, Yuji

AU - Furukawa, Keiko

AU - Furukawa, Koichi

AU - Hsu, Fong-Fu

AU - Adlercreutz, Dietlind

AU - Weadge, Joel

AU - Palcic, Monica M

AU - Wang, Peng G

AU - Levery, Steven B

AU - Zhou, Dapeng

N1 - Keywords: Animals; Galactosyltransferases; Gene Expression; Genomics; Globosides; Glycosphingolipids; Hydrogen-Ion Concentration; Ligands; Mice; Mice, Knockout; Natural Killer T-Cells; Thymus Gland; alpha-Galactosidase; beta-Hexosaminidase beta Chain

PY - 2009

Y1 - 2009

N2 - Invariant NKT cells are a hybrid cell type of Natural Killer cells and T cells, whose development is dependent on thymic positive selection mediated by double positive thymocytes through their recognition of natural ligands presented by CD1d, a nonpolymorphic, non-MHC, MHC-like antigen presenting molecule. Genetic evidence suggested that beta-glucosylceramide derived glycosphingolipids (GSLs) are natural ligands for NKT cells. N-butyldeoxygalactonojirimycin (NB-DGJ), a drug that specifically inhibits the glucosylceramide synthase, inhibits the endogenous ligands for NKT cells. Furthermore, we and others have found a beta-linked glycosphingolipid, isoglobotriaosylceramide (iGb3), is a stimulatory NKT ligand. The iGb3 synthase knockout mice have a normal NKT development and function, indicating that other ligands exist and remain to be identified. In this study, we have performed a glycosphingolipidomics study of mouse thymus, and studied mice mutants which are deficient in beta-hexosaminidase b or alpha-galactosidase A, two glycosidases that are up- and downstream agents of iGb3 turnover, respectively. Our mass spectrometry methods generated a first database for glycosphingolipids expressed in mouse thymus, which are specifically regulated by rate-limiting glycosidases. Among the identified thymic glycosphingolipids, only iGb3 is a stimulatory ligand for NKT cells, suggesting that large-scale fractionation, enrichment and characterization of minor species of glycosphingolipids are necessary for identifying additional ligands for NKT cells. Our results also provide early insights into cellular lipidomics studies, with a specific focus on the important immunological functions of glycosphingolipids.

AB - Invariant NKT cells are a hybrid cell type of Natural Killer cells and T cells, whose development is dependent on thymic positive selection mediated by double positive thymocytes through their recognition of natural ligands presented by CD1d, a nonpolymorphic, non-MHC, MHC-like antigen presenting molecule. Genetic evidence suggested that beta-glucosylceramide derived glycosphingolipids (GSLs) are natural ligands for NKT cells. N-butyldeoxygalactonojirimycin (NB-DGJ), a drug that specifically inhibits the glucosylceramide synthase, inhibits the endogenous ligands for NKT cells. Furthermore, we and others have found a beta-linked glycosphingolipid, isoglobotriaosylceramide (iGb3), is a stimulatory NKT ligand. The iGb3 synthase knockout mice have a normal NKT development and function, indicating that other ligands exist and remain to be identified. In this study, we have performed a glycosphingolipidomics study of mouse thymus, and studied mice mutants which are deficient in beta-hexosaminidase b or alpha-galactosidase A, two glycosidases that are up- and downstream agents of iGb3 turnover, respectively. Our mass spectrometry methods generated a first database for glycosphingolipids expressed in mouse thymus, which are specifically regulated by rate-limiting glycosidases. Among the identified thymic glycosphingolipids, only iGb3 is a stimulatory ligand for NKT cells, suggesting that large-scale fractionation, enrichment and characterization of minor species of glycosphingolipids are necessary for identifying additional ligands for NKT cells. Our results also provide early insights into cellular lipidomics studies, with a specific focus on the important immunological functions of glycosphingolipids.

U2 - 10.1021/pr801040h

DO - 10.1021/pr801040h

M3 - Journal article

C2 - 19284783

SN - 1535-3893

VL - 8

SP - 2740

EP - 2751

JO - Journal of Proteome Research

JF - Journal of Proteome Research

IS - 6

ER -

Immunologic glycosphingolipidomics and NKT cell development in mouse thymus

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