Florida Atlantic University, Charles E. Schmidt College of Medicine, Integrated Medical Science Department, Florida Atlantic University, 777 Glades Road, PO Box 3091, Boca Raton, FL 33431, USA.
Florida Atlantic University, Charles E. Schmidt College of Medicine, Integrated Medical Science Department, Florida Atlantic University, 777 Glades Road, PO Box 3091, Boca Raton, FL 33431, USA.
Immunol Lett. 2018 Jan;193:58-66. doi: 10.1016/j.imlet.2017.10.015. Epub 2017 Dec 1.
Most current prophylactic vaccines confer protection primarily through humoral immunity. Indeed, aluminum salts which have been widely used as adjuvants in vaccines primarily enhance Th2-driven antibody responses. Therefore, new vaccines formulation is moving toward a careful selection of adjuvants that also elicit significant Th1 or Tc1 responses. Several TLR agonists have been tested as potential new adjuvants in clinical and preclinical studies with some efficacy. These studies suggest that combining more than one of TLR ligands enhances the magnitude of immune responses to cancer and infectious disease.
In order to evaluate the synergistic effect of TLR agonists for effective induction of cellular immunity, we investigated the effects of single and/or combined TLR agonists on monocyte-derived DC maturation, DC-NK crosstalk and ultimately naïve T cells polarization into effector T cells.
Among the adjuvants tested, we found that TLR3, TLR4, TLR7/8 and TLR8 agonists were the most effective adjuvants to increase the expression levels of antigen-presenting, co-stimulatory molecules and production of cytokines by maturing DCs. When combined, TLR3+8 and TLR4+8 synergistically optimized DC maturation and IFN-γ secretion from NK cells co-cultured with DCs. Interestingly, co-culture of DC-NK-T treated with aluminum salt produced the highest percentage of effector memory CFSE-CCR7- Th1 cells whereas TLR3+8 and TLR4+8 treated co-cultures produced the highest percentage of effector memory CFSE-CCR7- Tc1 cells producing IFN-γ. Finally, while both TLR3+8 or TLR4+8 treated co-cultures generated similar frequency of Th1 and Tc1 effector cells, the effector cells from the latter co-culture produced quantitatively more IFN-γ in the supernatant.
Our data indicate that if in need of an enhanced DC-NK mediated cellular immunity one may select TLR agonists with defined synergistic effects.
大多数当前的预防性疫苗主要通过体液免疫提供保护。事实上,已广泛用作疫苗佐剂的铝盐主要增强了 Th2 驱动的抗体反应。因此,新疫苗制剂的开发方向是精心选择佐剂,这些佐剂还可以引起显著的 Th1 或 Tc1 反应。一些 TLR 激动剂已在临床前研究中作为潜在的新型佐剂进行了测试,具有一定的疗效。这些研究表明,联合使用多种 TLR 配体可增强针对癌症和传染病的免疫反应的幅度。
为了评估 TLR 激动剂对有效诱导细胞免疫的协同作用,我们研究了单一和/或组合 TLR 激动剂对单核细胞衍生的 DC 成熟、DC-NK 串扰以及最终幼稚 T 细胞向效应 T 细胞极化的影响。
在所测试的佐剂中,我们发现 TLR3、TLR4、TLR7/8 和 TLR8 激动剂是最有效的佐剂,可增加成熟 DC 表达抗原呈递、共刺激分子的水平和细胞因子的产生。联合使用时,TLR3+8 和 TLR4+8 可协同优化 DC 成熟和与 DC 共培养的 NK 细胞产生 IFN-γ。有趣的是,用铝盐处理的 DC-NK-T 共培养物产生了最高比例的效应记忆 CFSE-CCR7- Th1 细胞,而 TLR3+8 和 TLR4+8 处理的共培养物则产生了最高比例的产生 IFN-γ的效应记忆 CFSE-CCR7- Tc1 细胞。最后,虽然 TLR3+8 或 TLR4+8 处理的共培养物均产生了相似频率的 Th1 和 Tc1 效应细胞,但后者共培养物产生的 IFN-γ在培养上清液中的量更多。
我们的数据表明,如果需要增强 DC-NK 介导的细胞免疫,则可以选择具有明确定义协同作用的 TLR 激动剂。