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

尽管BCG作为抗结核疫苗被广泛使用，但其诱导CD1依赖性、脂质特异性免疫应答的能力尚未被研究。在接种卡介苗的豚鼠中，脾脏T细胞对分枝杆菌衍生的蛋白抗原的增殖作出反应，但对脂质抗原没有反应。然而，在使用豚鼠CD 1转染的成纤维细胞作为靶细胞的细胞溶解试验中，脾T细胞能够识别并杀死BCG脂质脉冲的靶细胞，但不能识别并杀死表达CD 1b2、CD 1b3或CD 1b4同种型的非脉冲靶细胞。因此，活卡介苗疫苗接种导致细胞毒性T细胞的激活，这些细胞以CD 1依赖性方式特异性识别卡介苗衍生的脂质，这与我们之前在卡介苗接种的人类个体循环中识别CD 8阳性、CD 1限制性T细胞是平行的。这些结果证明了BCG诱导脂质特异性T细胞应答的突出能力，这是以前从未被认识到的。除了细胞介导的免疫外，在BCG接种的豚鼠中检测到对分枝杆菌衍生的脂质（包括必需的细胞壁糖脂，脂阿拉伯甘露聚糖）的IgG抗体应答。鉴于脂阿拉伯甘露聚糖抑制宿主免疫的几个方面，允许细菌在宿主中存活，特异性抗体的产生可能有助于防止分枝杆菌感染。总之，从这项研究中获得的结果强调了脂质特异性获得性免疫在宿主防御结核病中的作用，因此，提出了新型脂质抗结核疫苗的重要可能性。

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.