Immunologic Glycosphingolipidomics and NKT Cell Development in Mouse Thymus

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• 作者：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
• 刊名：Journal of Proteome Research
• 出版年：2009
• 出版时间：June 5, 2009
• 年：2009
• 卷：8
• 期：6
• 页码：2740-2751
• 全文大小：301K
• 年卷期：v.8,no.6(June 5, 2009)
• ISSN：1535-3907

文摘

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.