Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Infect Immun. 2010 Apr;78(4):1610-7. doi: 10.1128/IAI.00002-10. Epub 2010 Feb 1.
The current Bacillus anthracis vaccine consists largely of protective antigen (PA), the protein of anthrax toxin that mediates entry of edema factor (EF) or lethal factor (LF) into cells. PA induces protective antibody (Ab)-mediated immunity against Bacillus anthracis but has limited efficacy and duration. We previously demonstrated that activation of CD1d-restricted natural killer-like T cells (NKT) with a CD1d-binding glycolipid led to enhanced Ab titers specific for foreign antigen (Ag). We therefore tested the hypothesis that activation of NKT cells with the CD1d ligand (alpha-galactosylceramide [alpha-GC]) at the time of immunization improves PA-specific Ab responses. We observed that alpha-GC enhanced PA-specific Ab titers in C57BL/6 mice. In CD1d(-/-) mice deficient in type I and type II NKT cells the anti-PA Ab response was diminished. In Jalpha281(-/-) mice expressing CD1d but lacking type I alpha-GC-reactive NKT cells, alpha-GC did not enhance the Ab response. In vitro neutralization assays were performed and showed that the Ab titers correlated with protection of macrophages against anthrax lethal toxin (LT). The neutralization capacity of the Ab was further tested in lethal challenge studies, which revealed that NKT activation leads to enhanced in vivo protection against LT. Anti-PA Ab titers, neutralization, and protection were then measured over a period of several months, and this revealed that NKT activation leads to a sustained protective Ab response. These results suggest that NKT-activating CD1d ligands could be exploited for the development of improved vaccines for Bacillus anthracis that increase not only neutralizing Ab titers but also the duration of the protection afforded by Ab.
目前的炭疽芽孢杆菌疫苗主要由保护性抗原 (PA) 组成，PA 是炭疽毒素的蛋白，介导水肿因子 (EF) 或致死因子 (LF) 进入细胞。PA 诱导针对炭疽芽孢杆菌的保护性抗体 (Ab) 介导的免疫，但效力和持续时间有限。我们之前证明，用 CD1d 结合糖脂激活 CD1d 限制性自然杀伤样 T 细胞 (NKT) 可导致针对外来抗原 (Ag) 的 Ab 滴度升高。因此，我们测试了在免疫时用 CD1d 配体 (α-半乳糖基神经酰胺 [α-GC]) 激活 NKT 细胞是否可以改善 PA 特异性 Ab 反应的假说。我们观察到 α-GC 增强了 C57BL/6 小鼠中的 PA 特异性 Ab 滴度。在缺乏 I 型和 II 型 NKT 细胞的 CD1d(-/-) 小鼠中，抗-PA Ab 反应减弱。在表达 CD1d 但缺乏 I 型 α-GC 反应性 NKT 细胞的 Jalpha281(-/-) 小鼠中，α-GC 并未增强 Ab 反应。进行了体外中和测定，结果表明 Ab 滴度与对抗炭疽致死毒素 (LT) 的巨噬细胞的保护相关。Ab 的中和能力在致死性挑战研究中进一步进行了测试，结果表明 NKT 激活可导致对 LT 的体内保护增强。然后在几个月的时间内测量了抗-PA Ab 滴度、中和和保护作用，这表明 NKT 激活可导致持续的保护性 Ab 反应。这些结果表明，NKT 激活的 CD1d 配体可用于开发针对炭疽芽孢杆菌的改良疫苗，不仅增加中和 Ab 滴度，而且延长 Ab 提供的保护时间。
