Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
J Biol Chem. 2011 May 13;286(19):16800-6. doi: 10.1074/jbc.M110.217224. Epub 2011 Mar 25.
Delayed-type hypersensitivity (DTH) is marked by high levels of protein antigen-specific T cell responses in sensitized individuals. Recent evidence has revealed a distinct pathway for T cell immunity directed against glycolipid antigens, but DTH to this class of antigen has been undetermined and difficult to prove due to their insolubility in aqueous solutions. Here, glucose monomycolate (GMM), a highly hydrophobic glycolipid of the cell wall of mycobacteria, was dispersed in aqueous solutions in the form of octaarginine-modified liposomes and tested for its ability to elicit cutaneous DTH responses in bacillus Calmette-Guerin (BCG)-immunized guinea pigs. After an intradermal challenge with the GMM liposome, a significant skin induration was observed in BCG-immunized, but not mock-treated, animals. The skin reaction peaked at around 2 days with local infiltration by mononuclear cells, and therefore, the response shared basic features with the classical DTH to protein antigens. Lymph node T cells from BCG-immunized guinea pigs specifically increased IFN-γ transcription in response to the GMM liposome, and this response was completely blocked by antibodies to CD1 lipid antigen-presenting molecules. Finally, whereas the T cells increased transcription of both T helper (Th) 1-type (IFN-γ and TNF-α) and Th2-type (IL-5 and IL-10) cytokines in response to the purified protein derivative or tuberculin, their GMM-specific response was skewed to Th1-type cytokine production known to be critical for protection against tuberculosis. Thus, our study reveals a novel form of DTH with medical implications.
迟发型超敏反应（DTH）的特点是致敏个体中高水平的蛋白抗原特异性 T 细胞反应。最近的证据揭示了针对糖脂抗原的独特 T 细胞免疫途径，但由于此类抗原在水溶液中不溶解，因此 DTH 尚未确定且难以证明。在这里，葡萄糖单胞酸酯（GMM）是分枝杆菌细胞壁的一种高度疏水性糖脂，被八精氨酸修饰的脂质体分散在水溶液中，并在卡介苗（BCG）免疫豚鼠中测试其引发皮肤 DTH 反应的能力。用 GMM 脂质体进行皮内挑战后，在 BCG 免疫但未进行模拟处理的动物中观察到明显的皮肤硬结。皮肤反应在大约 2 天时达到峰值，伴有单核细胞浸润，因此，该反应与经典的蛋白抗原 DTH 具有基本特征。BCG 免疫豚鼠的淋巴结 T 细胞特异性增加对 GMM 脂质体的 IFN-γ 转录，而针对 CD1 脂质抗原呈递分子的抗体完全阻断了该反应。最后，虽然 T 细胞对纯化蛋白衍生物或结核菌素的反应增加了 Th1 型（IFN-γ 和 TNF-α）和 Th2 型（IL-5 和 IL-10）细胞因子的转录，但它们对 GMM 的特异性反应偏向于 Th1 型细胞因子的产生，这对于保护机体免受结核病至关重要。因此，我们的研究揭示了一种具有医学意义的新型 DTH 形式。
