CD1d-Dependent B-Cell Help by NK-Like T Cells Leads to Enhanced and Sustained Production of Bacillus anthracis Lethal Toxin-Neutralizing Antibodies
CD1d-Dependent B-Cell Help by NK-Like T Cells Leads to Enhanced and Sustained Production of Bacillus anthracis Lethal Toxin-Neutralizing Antibodies
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DOI：
10.1128/iai.00002-10
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发表时间：
2010-04-01
影响因子：
3.1
通讯作者：
Lang, Mark L.
中科院分区：
文献类型：
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作者：
Devera, T. Scott;Aye, Lindsay M.;Lang, Mark L.
目前的炭疽杆菌疫苗主要由保护性抗原（PA）组成，PA是炭疽毒素的蛋白质，介导水肿因子（EF）或致死因子（LF）进入细胞。PA诱导针对炭疽杆菌的保护性抗体（Ab）介导的免疫，但效力和持续时间有限。我们以前证明，CD 1d-限制性天然类T细胞（NKT）与CD 1d-结合糖脂的激活导致增强的抗体滴度特异性的外来抗原（Ag）。因此，我们检验了以下假设：在免疫时用CD 1d配体（α-半乳糖神经酰胺[α-GC]）激活NKT细胞可改善PA特异性Ab应答。我们观察到α-GC增强C57 BL/6小鼠中PA特异性Ab滴度。在缺乏I型和II型NKT细胞的CD 1d（-/-）小鼠中，抗PA Ab反应减弱。在表达CD 1d但缺乏I型α-GC反应性NKT细胞的J α 281（-/-）小鼠中，α-GC不增强Ab反应。体外中和试验表明，抗体滴度与巨噬细胞对炭疽致死毒素（LT）的保护相关。在致死性攻击研究中进一步测试了Ab的中和能力，结果表明NKT激活导致增强的体内抗LT保护。然后在几个月的时间内测量抗PA Ab滴度、中和和保护，结果表明NKT激活导致持续的保护性Ab应答。这些结果表明，NKT活化CD 1d配体可用于开发改进的炭疽杆菌疫苗，不仅增加中和抗体滴度，而且增加抗体提供的保护的持续时间。
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 J alpha 281(-/-) 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.