New anti-tuberculosis vaccine strategies by the use of the CD1-lipid antigen presentation pathway

尽管卡介苗已被广泛用作抗结核疫苗，但其诱导CD1依赖的、脂类特异的免疫反应的能力尚未得到检验。在接种卡介苗的豚鼠中，脾T细胞对分枝杆菌衍生蛋白抗原有增殖反应，但对脂肪抗原无反应。然而，在以转导CD1的豚鼠成纤维细胞为靶细胞的细胞溶解试验中，脾T细胞能够识别和杀伤表达CD1b2、CD1b3或CD1b4亚型的卡介苗脂脉冲靶细胞，但不能识别和杀伤非脉冲靶细胞。因此，活的卡介苗接种导致细胞毒性T细胞的激活，这种细胞毒性T细胞以CD1依赖的方式识别卡介苗衍生的脂类，这与我们之前在卡介苗接种的人的循环中发现的CD8阳性、CD1受限的T细胞是平行的。这些结果表明，卡介苗能够诱导前所未有的脂类特异性T细胞反应。除了细胞免疫外，在接种卡介苗的豚鼠中还检测到对分枝杆菌衍生的脂类的抗体反应，包括一种重要的细胞壁糖脂--阿拉伯甘露聚糖。鉴于脂肪阿拉伯甘露聚糖抑制宿主免疫的几个方面，允许细菌在宿主中生存，产生特定的抗体可能有助于保护免受分枝杆菌感染。综上所述，本研究结果强调了脂类特异性获得性免疫在抗结核宿主防御中的作用，从而为新型脂类抗结核疫苗的研制提供了重要的可能性。

Despite the extensive use of BCG as an anti-tuberculosis vaccine, its ability to induce CD1-dependent, lipid-specific immune responses has not been examined. In guinea pigs vaccinated with BCG, splenic T cells responded by proliferation to mycobacteria-derived protein antigens, but not to lipid antigens. However, in cytolytic assays using guinea pig CD1-transfected fibroblasts as target cells, splenic T cells were able to recognize and kill BCG lipid-pulsed, but not unpulsed, target cells that express either CD1b2,CD1b3, or CD1b4 isoforms. Thus, live BCG vaccination resulted in activation of cytotoxic T cells that specifically recognize BCG-derived lipids in a CD1-dependent manner, which was parallel to our previous identification of CD8-positive, CD1-restricted T cells in the circulation of BCG-vaccinated human individuals. These results demonstrated an outstanding ability of BCG to induce lipid-specific T cell responses that had never been appreciated previously.In addition to the cell-mediated immunity, IgG antibody responses to mycobacteria-derived lipids, including an essential cell wall glycolipid, lipoarabinomannan, were detected in BCG-vaccinated guinea pigs. Given that lipoarabinomannan suppresses several aspects of host immunity, allowing the bacteria to survive in the host, production of specific antibodies may contribute to protection against mycobacterial infection. Taken together, results obtained from this study underscore a role for the lipid-specific acquired immunity in host defense against tuberculosis, and thus, raise the important possibility for a new type of lipid-based anti-tuberculosis vaccines.