A Microbial Glycolipid Functions as a New Class of Target Antigen for Delayed-type Hypersensitivity*
A Microbial Glycolipid Functions as a New Class of Target Antigen for Delayed-type Hypersensitivity*
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DOI：
10.1074/jbc.m110.217224
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
T. Komori;Takashi Nakamura;I. Matsunaga;D. Morita;Y. Hattori;H. Kuwata;N. Fujiwara;K. Hiromatsu;H. Harashima;M. Sugita
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文献类型：
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作者：
T. Komori;Takashi Nakamura;I. Matsunaga;D. Morita;Y. Hattori;H. Kuwata;N. Fujiwara;K. Hiromatsu;H. Harashima;M. Sugita
迟发性超敏反应(DTH)在致敏个体中表现为高水平的蛋白抗原特异性T细胞反应。最近的证据表明，针对糖脂抗原的T细胞免疫有一条独特的途径，但由于这类抗原在水溶液中的不溶性，对这类抗原的DTH一直没有确定，也很难证明。在此，将分枝杆菌细胞壁的一种高度疏水的糖脂葡萄糖单菌酯(GMM)以八精氨酸修饰的脂质体的形式分散在水溶液中，并在卡介苗(BCG)免疫的豚鼠身上测试了其诱导皮肤DTH反应的能力。在用GMM脂质体皮内攻击后，在卡介苗免疫但未模拟治疗的动物中观察到显著的皮肤硬化。皮肤反应在2d左右达到高峰，局部有单个核细胞浸润，因此，对蛋白质抗原的反应与经典的DTH反应具有相同的基本特征。来自卡介苗免疫的豚鼠的淋巴T细胞特异性地增加干扰素-γ的转录，这一反应被CD1脂抗原呈递分子的抗体完全阻断。最后，尽管T细胞对纯化蛋白衍生物或结核菌素的反应增加了辅助性T细胞(Th)1型(干扰素-γ和肿瘤坏死因子-α)和Th2型(IL-5和IL-10)细胞因子的转录，但它们的GMM特异性反应偏向于Th1型细胞因子的产生，而Th1型细胞因子是已知的对预防结核病至关重要的。因此，我们的研究揭示了一种具有医学意义的新型DTH。
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.