Immunologic glycosphingolipidomics and NKT cell development in mouse thymus.
Immunologic glycosphingolipidomics and NKT cell development in mouse thymus.
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DOI：
10.1021/pr801040h
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发表时间：
2009-06
影响因子：
4.4
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Li Y;Thapa P;Hawke D;Kondo Y;Furukawa K;Furukawa K;Hsu FF;Adlercreutz D;Weadge J;Palcic MM;Wang PG;Levery SB;Zhou D
不变自然杀伤T细胞（iNKT细胞）是自然杀伤细胞和T细胞的一种混合细胞类型，其发育依赖于双阳性胸腺细胞介导的胸腺阳性选择，双阳性胸腺细胞通过识别由CD1d（一种非多态性、非主要组织相容性复合体（MHC）、类似MHC的抗原呈递分子）呈递的天然配体来实现这一过程。遗传学证据表明，β -葡萄糖脑苷脂衍生的鞘糖脂（GSLs）是iNKT细胞的天然配体。N -丁基脱氧半乳糖野尻霉素（NB - DGJ）是一种特异性抑制葡萄糖脑苷脂合酶的药物，它可抑制iNKT细胞的内源性配体。此外，我们及其他研究人员发现一种β -连接的鞘糖脂，异球三糖神经酰胺（iGb3），是一种刺激性的iNKT配体。iGb3合酶敲除小鼠具有正常的iNKT细胞发育和功能，这表明存在其他配体且有待鉴定。在本研究中，我们对小鼠胸腺进行了鞘糖脂组学研究，并研究了β -己糖胺酶b或α -半乳糖苷酶A缺陷的小鼠突变体，这两种糖苷酶分别是iGb3代谢的上游和下游因子。我们的质谱方法生成了首个小鼠胸腺表达的鞘糖脂数据库，这些鞘糖脂受到限速糖苷酶的特异性调控。在已鉴定的胸腺鞘糖脂中，只有iGb3是iNKT细胞的刺激性配体，这表明对鞘糖脂的微量种类进行大规模分离、富集和特性鉴定对于鉴定iNKT细胞的其他配体是必要的。我们的研究结果也为细胞脂质组学研究提供了早期见解，尤其关注鞘糖脂的重要免疫功能。
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 non-polymorphic, 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 down-stream agents of iGb3 turnover, respectively. Our mass spectrometry methods generated a first database for glycosphingolipids expressed by 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, be 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.
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DOI：
10.1084/jem.20060921
发表时间：
2006-10-02
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Gadola SD;Silk JD;Jeans A;Illarionov PA;Salio M;Besra GS;Dwek R;Butters TD;Platt FM;Cerundolo V
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DOI：
10.1073/pnas.94.6.2540
发表时间：
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影响因子：
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DOI：
10.1016/j.jasms.2003.12.007
发表时间：
2004-04-01
影响因子：
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