Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169⁺ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3^-/- mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans.

中文翻译：

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CD169 +淋巴结常驻巨噬细胞在AS01 QS-21成分佐剂中的核心作用。

皂苷代表一类有希望的疫苗佐剂。QS-21与TLR4-配体MPL一起是佐剂系统AS01的一部分，AS01是显示出临床疗效的疟疾和带状疱疹候选疫苗的关键组成部分。但是，对于这种脂质体制剂中QS-21的作用机理了解甚少。肌肉内免疫后，我们观察到QS-21在CD169 ^+中迅速积累引流淋巴结的常驻巨噬细胞，引起局部先天免疫反应。这些细胞的消耗废除了QS-21介导的先天细胞募集到淋巴结，树突状细胞（DC）表型成熟以及对T细胞的佐剂作用和对共同施用的抗原的抗体反应。DC通过QS-21直接参与T细胞的启动，而不是驻留在淋巴结中的巨噬细胞，如Batf3 ^-/-中抗原特异性T细胞反应的减少所揭示的那样^。老鼠。进一步的分析表明，QS-21的佐剂作用至少部分通过HMGB1的局部释放而依赖于Caspase-1和MyD88途径的整合。综上所述，这项工作揭示了淋巴结前哨巨噬细胞在控制已证明可改善人类疫苗反应的分子的佐剂作用中的关键作用。