Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525GA, Nijmegen, The Netherlands.
Cell Mol Life Sci. 2022 Apr 9;79(5):231. doi: 10.1007/s00018-022-04253-x.
Saponin-based adjuvants (SBAs) are promising new adjuvants that stand out as they not only enforce CD4 + T cell-mediated immunity and antibody responses, but also induce an unprecedented level of antigen cross-presentation by dendritic cells (DC) and subsequent CD8 + T cell activation. We discovered that SBA's ability to boost cross-presentation depends on the induction of lipid bodies (LBs). Moreover, the MHCIICD11b DC subset was identified to be most responsive to SBA-induced cross-presentation. The aim is to further unravel the mechanisms behind the induction of DC cross-presentation by SBAs. Here we show that SBAs specifically induce the PKR-like Endoplasmic Reticulum kinase (PERK) pathway and that SBA-induced DC cross-presentation is dependent on activation of the PERK pathway. PERK activation and LB formation are both crucial for SBA-induced cross-presentation and PERK inhibition has little or no effect on SBA-induced LB formation. SBA's responsiveness, LB formation and PERK activation are specific for the MHCIICD11b DCs. These findings contribute to understanding the pathways involved in SBA-induced cross-presentation and immune activation which will ultimately lead to the development of vaccines with improved efficiency and safety.
基于皂素的佐剂（SBAs）是很有前途的新型佐剂，它们不仅能增强 CD4+T 细胞介导的免疫和抗体反应，还能诱导树突状细胞（DC）前所未有的抗原交叉呈递水平，进而激活 CD8+T 细胞。我们发现，SBA 增强交叉呈递的能力取决于脂滴（LBs）的诱导。此外，鉴定出 MHCIICD11b DC 亚群对 SBA 诱导的交叉呈递反应最敏感。目的是进一步阐明 SBAs 诱导 DC 交叉呈递的机制。在这里，我们表明 SBAs 特异性诱导 PKR 样内质网激酶（PERK）途径，并且 SBA 诱导的 DC 交叉呈递依赖于 PERK 途径的激活。PERK 激活和 LB 形成对于 SBA 诱导的交叉呈递都是至关重要的，而 PERK 抑制对 SBA 诱导的 LB 形成几乎没有影响。SBA 的反应性、LB 形成和 PERK 激活都是 MHCIICD11b DC 所特有的。这些发现有助于理解 SBA 诱导的交叉呈递和免疫激活涉及的途径，这最终将导致开发出具有更高效率和安全性的疫苗。
