Glycolipid Presentation by CD1d

糖神经酰胺作为CD1家族递呈的T细胞抗原具有重要的免疫功能 与脂质结合的MHC类分子。例如，ct-半乳糖基神经酰胺(Otgc)可特异性激活 调节性NKT细胞，通过释放Th1或Th2细胞因子来调节各种疾病 条件。其他糖基神经酰胺可能会引起与多发性硬化症相关的适应性T细胞反应。 因此，该计划项目使用糖基神经酰胺作为模型抗原家族来研究 CD1D分子提呈糖脂抗原的潜在临床应用。 涵盖糖脂合成化学、蛋白质表达、生物物理学的多学科方法 结构生物学以及细胞免疫学和细胞生物学已经组装完毕。合成的 将产生NKT细胞抗原AGC的变种，以研究其佐剂的结构决定因素 属性。我们将使用新的方法来可视化细胞的摄取和贩运、CD1加载和TCR 糖基神经酰胺的结合，并将寻找具有选择性Th1或Th2佐剂特性的新变体 调节I型糖尿病、实验性脑脊髓炎和癌症等疾病的表达。在……里面 除了天然的NKT细胞对o_GC的反应外，我们还将探讨其多样性和特异性 糖脂特异性适应性TCR谱系，这是设计糖脂特异性T细胞疫苗的先决条件。这个 具体研究项目如下。项目1，Savage：OGC结构变体的设计 选择性Th1或Th2特性。项目2，Teyton：糖基神经酰胺的生物物理和结构方面 与CDLD和TCR的相互作用。项目3，Bendelac：与以下项目相关的T细胞汇编和功能 糖基神经酰胺在小鼠体内的识别和糖基神经酰胺的细胞内转运特性。

Glycosylceramides perform important immunological functions as T cell antigens presented by CD 1, a family of lipid-binding MHC-like molecules. For example, an ct-galactosylceramide (otGC) specifically activates regulatory NKT cells which modulate, through the release of either Thl or Th2 cytokines, various disease conditions. Other glycosylceramides may elicit adaptive T cell responses involved in Multiple Sclerosis. Thus, the program project uses glycosylceramides as a model antigen family to study fundamental issues of glycolipid antigen presentation by CD 1d molecules with potential clinical applications. A multidisciplinary approach encompassing glycolipid synthetic chemistry, protein expression, biophysics and structural biology, as well as cellular immunology and cell biology, has been assembled. Synthetic variants of aGC, the NKT cell antigen, will be generated to study the structural determinants of their adjuvant properties. We will use new approaches to visualize the cellular uptake and trafficking, CD1 loading and TCR binding of glycosylceramides and will search for new variants with selective Thl or Th2 adjuvant properties modulating expression of diseases such as type I diabetes, experimental encephalomyelitis and cancer. In addition to the innate NKT cell response to o_GC, we also will probe the diversity and specificity of the glycolipid-specific adaptive TCR repertoire, a prerequisite to design glycolipid-specific T cell vaccines. The individual research projects are as follows. Project 1, Savage: Design of ocGC structural variants with selective Thl or Th2 properties. Project 2, Teyton: Biophysical and structural aspects of glycosylceramide interaction with CDld and TCR. Project 3, Bendelac: T cell repertoire and functions associated with glycosylceramide recognition in vivo in mice and intracellular trafficking properties of glycosylceramides.