利用exo-Glycal化學合成含限制構形α-半乳糖神經醯胺 類似物並且探討其對於自然殺手T細胞之生物活性

Abstract

自然殺手T (NKT) 細胞是會同時表現T細胞受器及自然殺手細胞標記的一種T淋巴細胞。NKT細胞藉由非典型主要組織相容複合體 (MHC) I分子：CD1d 辨識醣脂質抗原。目前已知人類或是老鼠CD1d所呈獻的醣脂質之中，α-半乳糖苷神經醯胺 (α-GalCer) 具有最強的免疫刺激活性。α-GalCer是由海棉中的天然物加以衍生而來的分子，早期發現其具有抗癌活性。在後來的研究中指出α-GalCer可以與CD1d結合，藉由T細胞受器刺激NKT細胞，進而釋放出會產生TH1或TH2免疫反應的細胞激素，例如干擾素-γ (IFN-γ) 或間白素-4 ( IL-4)。 修飾α-GalCer的結構可能會導致刺激活性的改變，或是使細胞激素的釋放產生變化。許多報導已經描述了α-GalCer被NKT細胞辨視所需要的結構特徵，而在這些研究當中，卻鮮少有人去探討醣基構形對於活性的影響。在此，我們設計及合成了一系列含限制構形的α-GalCer類似物，並且以不同的脂肪醯鏈加以修飾。在醣化反應的關鍵步驟中，則使用exo-glycals 化學提供高度的立體選擇性。我們也藉由測試細胞激素的釋放以探討這些分子是否具有刺激NKT 細胞的能力。

Natural killer T (NKT) cells are a novel subset of T cells that express both T-cell and natural killer (NK)-cell markers. NKT cells recognize non-classical MHC class I molecule CD1d in conjunction with glycolipid antigens. Among the reported glycolipids presented by human or mouse CD1d, α-galactosylceramide (α-GalCer) shows the highest immune-stimulatory activities. α-GalCer is derived from a marine sponge natural product and has been shown to possess antitumor activity. Further studies indicate that α-GalCer can bind to CD1d and activate NKT cells through T cell receptor (TCR) recognition to produce T helper 1 (TH1) and T helper 2 (TH2) cytokines, such as interferon-γ (IFN-γ) and interleukin-4 (IL-4), respectively. Modification of α-GalCer may alter the level of stimulatory activity and/or switch the cytokine pattern released by NKT cells. Several reports have described the structural requirement for α-GalCer recognition by CD1d-restricted NKT cells, but few of them studied the effect of sugar conformation. Herein we designed and synthesized conformationally constrained α-GalCer analogues with different fatty acyl chains. The key step employs the glycosylation of exo-glycals, offering the advantage of exclusive stereoselectivity. We also evaluated their ability to activate mouse NKT cells by measuring cytokine release profiles.