Modern vaccines have largely shifted from using whole, killed or attenuated pathogens to being based on subunit components. Since this diminishes immunogenicity, vaccine adjuvants that enhance the immune response to purified antigens are critically needed. Further advantages of adjuvants include dose sparing, increased vaccine efficacy in immunocompromised individuals and the potential to protect against highly variable pathogens by broadening the immune response. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists are highly promising as adjuvants in vaccines against life-threatening and complex diseases such as cancer, AIDS and malaria. TLRs are transmembrane receptors, which are predominantly expressed by innate immune cells. They can be classified into cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and intracellular TLRs (TLR3, TLR7, TLR8, TLR9), expressed on endosomal membranes. Besides a transmembrane domain, each TLR possesses a leucine-rich repeat (LRR) segment that mediates PAMP/DAMP recognition and a TIR domain that delivers the downstream signal transduction and initiates an inflammatory response. Thus, TLRs are excellent targets for adjuvants to provide a “danger” signal to induce an effective immune response that leads to long-lasting protection. The present review will elaborate on applications of TLR ligands as vaccine adjuvants and immunotherapeutic agents, with a focus on clinically relevant adjuvants.

中文翻译：

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TLR 激动剂作为针对癌症和传染病的疫苗佐剂


现代疫苗已基本上从使用完整的、灭活的或减毒的病原体转向基于亚单位成分。由于这会降低免疫原性，因此迫切需要增强对纯化抗原的免疫反应的疫苗佐剂。佐剂的其他优点包括节省剂量、提高免疫功能低下个体的疫苗效力以及通过扩大免疫反应来预防高度变异的病原体的潜力。由于能够将先天性免疫反应与适应性免疫反应联系起来，Toll 样受体 (TLR) 激动剂非常有希望作为疫苗佐剂来对抗癌症、艾滋病和疟疾等危及生命的复杂疾病。 TLR 是跨膜受体，主要由先天免疫细胞表达。它们可分为细胞表面（TLR1、TLR2、TLR4、TLR5、TLR6）和细胞内 TLR（TLR3、TLR7、TLR8、TLR9），在内体膜上表达。除了跨膜结构域外，每个 TLR 还具有介导 PAMP/DAMP 识别的富含亮氨酸重复序列 (LRR) 片段和传递下游信号转导并启动炎症反应的 TIR 结构域。因此，TLR 是佐剂的绝佳靶标，可以提供“危险”信号，诱导有效的免疫反应，从而产生持久的保护。本综述将详细阐述 TLR 配体作为疫苗佐剂和免疫治疗剂的应用，重点关注临床相关佐剂。