Regulation of Anthrax Toxin-Specific Antibody Titers by Natural Killer T Cell-Derived IL-4 and IFNγ
Regulation of Anthrax Toxin-Specific Antibody Titers by Natural Killer T Cell-Derived IL-4 and IFNγ
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DOI：
10.1371/journal.pone.0023817
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发表时间：
2011-08-17
期刊：
影响因子：
3.7
通讯作者：
Lang, Mark L.
中科院分区：
文献类型：
--
作者：
Devera, T. Scott;Joshi, Sunil K.;Lang, Mark L.
CD1d配体α - gc激活自然杀伤样T细胞（NKT）可增强炭疽毒素保护性Ag （PA）中和抗体的产生，但这种辅助作用的潜在机制尚不清楚。在目前的研究中，我们研究了Th1和Th2型反应在nkt介导的PA抗体反应增强中的作用。首先，研究了IL-4和IFN γ对pa特异性毒素中和抗体产生的贡献。通过免疫C57Bl/6对照IL-4（-/-）小鼠和IFN γ(-/-)小鼠，并进行被动血清转移实验，观察到含有pa特异性IgG1， IgG2b和IgG2c的血清在体外中和毒素并在体内具有保护作用。含有IgG2b和IgG2c的血清在体外能中和毒素，但在体内不足以起到保护作用。含有IgG1和IgG2b的血清在体外中和毒素，并在体内具有保护作用。因此，IgG1作为保护的一个很好的关联而出现。接下来，用PA单独或PA加th2倾斜的α - gc衍生物OCH免疫C57Bl/6小鼠。在C57Bl/6小鼠中，OCH适度增强了中和pa特异性IgG1反应。相反，IgG2b和IgG2c在PA/ och免疫的IL-4（-/-）小鼠中显著增强，但不具有保护作用。最后，骨髓嵌合体的产生使得NKT细胞不能表达IL-4或IFN γ。och增强的原发性IgG1反应需要nkt衍生的IL-4，但不需要召回反应。nkt衍生的IL-4和IFN γ也影响初级和回忆IgG2b和IgG2c滴度。这些数据表明，可以利用α - gc衍生物对Th2反应的靶向偏斜来优化炭疽疫苗接种。
Activation of Natural Killer-like T cells (NKT) with the CD1d ligand alpha-GC leads to enhanced production of anthrax toxin protective Ag (PA)-neutralizing Abs, yet the underlying mechanism for this adjuvant effect is not known. In the current study we examined the role of Th1 and Th2 type responses in NKT-mediated enhancement of antibody responses to PA. First, the contribution of IL-4 and IFN gamma to the production of PA-specific toxin-neutralizing Abs was examined. By immunizing C57Bl/6 controls IL-4(-/-) mice and IFN gamma(-/-) mice and performing passive serum transfer experiments, it was observed that sera containing PA-specific IgG1, IgG2b and IgG2c neutralized toxin in vitro and conferred protection in vivo. Sera containing IgG2b and IgG2c neutralized toxin in vitro but were not sufficient for protection in vivo. Sera containing IgG1 and IgG2b neutralized toxin in vitro and conferred protection in vivo. IgG1 therefore emerged as a good correlate of protection. Next, C57Bl/6 mice were immunized with PA alone or PA plus a Th2-skewing alpha-GC derivative known as OCH. Neutralizing PA-specific IgG1 responses were modestly enhanced by OCH in C57Bl/6 mice. Conversely, IgG2b and IgG2c were considerably enhanced in PA/OCH-immunized IL-4(-/-) mice but did not confer protection. Finally, bone marrow chimeras were generated such that NKT cells were unable to express IL-4 or IFN gamma. NKT-derived IL-4 was required for OCH-enhanced primary IgG1 responses but not recall responses. NKT-derived IL-4 and IFN gamma also influenced primary and recall IgG2b and IgG2c titers. These data suggest targeted skewing of the Th2 response by alpha-GC derivatives can be exploited to optimize anthrax vaccination.