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

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39 Scopus citations

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 β-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 β-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 β-hexosaminidase b or α-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 languageEnglish
Pages (from-to)2740-2751
Number of pages12
JournalJournal of Proteome Research
Volume8
Issue number6
DOIs
StatePublished - Jun 5 2009

Keywords

  • CD1d
  • Glycomics
  • Glycosphingolipids
  • Isoglobotriaosylceramide (iGb3)
  • Linear ion trap mass spectrometry
  • Lipidomics
  • Natural Killer T (NKT) cells
  • T cell receptor
  • iGb3 synthase

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    Li, Y., Thapa, P., Hawke, D., Kondo, Y., Furukawa, K., Furukawa, K., Hsu, F. F., Adlercreutz, D., Weadge, J., Palcic, M. M., Wang, P. G., Levery, S. B., & Zhou, D. (2009). Immunologic glycosphingolipidomics and NKT cell development in mouse thymus. Journal of Proteome Research, 8(6), 2740-2751. https://doi.org/10.1021/pr801040h