Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
Microbiol Spectr. 2022 Feb 23;10(1):e0114421. doi: 10.1128/spectrum.01144-21.
Vaccination through the upper respiratory tract (URT) is highly effective for the prevention of respiratory infectious diseases. Toll-like receptor (TLR)-based adjuvants are immunostimulatory and considered potential adjuvant candidates. However, the patterns of immune response to different TLRs at the URT have not been revealed. In this study, SPF mice were preexposed to TLR agonists intranasally to simulate the status of humans. Inflammatory response to TLR agonists and TLR signal-mediated adaptive immune responses were analyzed. The results revealed that similar to human tonsils, inflammatory response to stimulation with TLR4 or TLR2 agonist was attenuated in agonist-exposed mice but not in mice without this exposure. In contrast, TLR9 or TLR3 agonist preexposure did not affect the inflammatory response to restimulation by matching agonists. For the adaptive immune response, after agonist preexposure the antibody response to antigens adjuvanted with TLR4 or TLR2 agonist was substantially restricted, whereas, both antibody and T cell responses to antigens adjuvanted with TLR9 or TLR3 agonist were activated as robustly as in mice without agonist exposure. Moreover, we demonstrate that the mechanisms underlying the differential activation of TLRs are regulated at the level of TLR expression in innate and adaptive immune cells. These results indicate that TLRs on the cell surface (TLR4 and 2) and in the endolysosomal compartments (TLR9 and 3) display distinct immune response patterns. The findings provide important information for the use of TLR agonists as mucosal adjuvants and enhance our understanding of immune responses to bacterial and viral infections in the respiratory mucosa. Agonists of TLRs are potential adjuvant candidates for mucosal vaccination. We demonstrated that the TLR-mediated inflammatory and antibody responses in the URT of SPF mice exposed to extracellular TLR agonists were substantially restricted. In contrast, inflammatory and adaptive immune responses, including B and T cell activation, were not desensitized in mice exposed to intracellular TLR agonists. The distinct responsive patterns of extra and intracellular TLRs regulated at TLR expression in immune cells. The results indicated that TLRs differentially impact the innate and adaptive immune response in the URT, which contributes to the selection of TLR-based mucosal adjuvants and helps understand the difference between the immune response in bacterial and viral infections.
经上呼吸道（URT）接种疫苗对预防呼吸道传染病非常有效。 Toll 样受体（TLR）为基础的佐剂具有免疫刺激性，被认为是有潜力的佐剂候选物。然而，不同 TLR 在 URT 处的免疫反应模式尚未被揭示。在这项研究中，SPF 小鼠通过鼻腔内给予 TLR 激动剂预先暴露，以模拟人类的状态。分析 TLR 激动剂引起的炎症反应和 TLR 信号介导的适应性免疫反应。结果表明，类似于人类扁桃体，TLR4 或 TLR2 激动剂刺激引起的炎症反应在预先暴露于激动剂的小鼠中减弱，但在未暴露于激动剂的小鼠中则不会减弱。相比之下，TLR9 或 TLR3 激动剂预先暴露不会影响匹配激动剂再次刺激时的炎症反应。对于适应性免疫反应，在激动剂预先暴露后，TLR4 或 TLR2 激动剂佐剂的抗原抗体反应受到显著限制，而 TLR9 或 TLR3 激动剂佐剂的抗原抗体和 T 细胞反应则像未暴露于激动剂的小鼠一样强烈激活。此外，我们证明，TLR 差异激活的机制是在固有和适应性免疫细胞的 TLR 表达水平上调节的。这些结果表明，细胞表面（TLR4 和 2）和内溶酶体区室（TLR9 和 3）上的 TLR 显示出不同的免疫反应模式。这些发现为 TLR 激动剂作为黏膜佐剂的应用提供了重要信息，并增强了我们对呼吸道黏膜中细菌和病毒感染的免疫反应的理解。TLR 激动剂是黏膜疫苗接种的潜在佐剂候选物。我们证明，暴露于细胞外 TLR 激动剂的 SPF 小鼠 URT 中的 TLR 介导的炎症和抗体反应受到显著限制。相比之下，暴露于细胞内 TLR 激动剂的小鼠中，炎症和适应性免疫反应，包括 B 和 T 细胞激活，没有脱敏。免疫细胞中 TLR 表达调节的细胞外和细胞内 TLR 的不同反应模式。结果表明，TLR 在上呼吸道中以不同的方式影响固有和适应性免疫反应，这有助于选择 TLR 为基础的黏膜佐剂，并有助于理解细菌和病毒感染之间的免疫反应差异。
