Central Role of CD169(+) Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01.
Central Role of CD169(+) Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01.
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DOI：
10.1038/srep39475
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发表时间：
2016-12-20
影响因子：
4.6
通讯作者：
Didierlaurent AM
中科院分区：
文献类型：
--
作者：
Detienne S;Welsby I;Collignon C;Wouters S;Coccia M;Delhaye S;Van Maele L;Thomas S;Swertvaegher M;Detavernier A;Elouahabi A;Goriely S;Didierlaurent AM
皂苷代表一类有前途的疫苗佐剂。QS-21与TLR 4配体MPL一起是佐剂系统AS 01的一部分，佐剂系统AS 01是疟疾和带状疱疹候选疫苗的关键组分，显示出已证实的临床疗效。然而，QS-21在该脂质体制剂中的作用机制知之甚少。在肌内免疫后，我们观察到QS-21在引流淋巴结的CD 169+驻留巨噬细胞中迅速积累，在那里它引起局部先天性免疫应答。这些细胞的消耗消除了QS-21介导的先天性细胞向淋巴结的募集、树突状细胞（DC）表型成熟以及对T细胞和抗体对共同施用的抗原的应答的佐剂作用。DC而不是淋巴结驻留的巨噬细胞直接参与QS-21的T细胞引发，如Batf 3 −/−小鼠中抗原特异性T细胞应答的降低所揭示的。进一步分析表明，QS-21的佐剂效应依赖于Caspase-1和MyD 88通路的整合，至少部分通过局部释放HMGB 1。总之，这项工作揭示了淋巴结哨兵巨噬细胞在控制一种分子的佐剂效应中的关键作用，这种分子被证明可以改善人类的疫苗反应。
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.
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