CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01.
CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01.
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DOI：
10.3389/fimmu.2020.606805
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发表时间：
2020
影响因子：
7.3
通讯作者：
Lambrecht BN
中科院分区：
文献类型：
--
作者：
Bosteels C;Fierens K;De Prijck S;Van Moorleghem J;Vanheerswynghels M;De Wolf C;Chalon A;Collignon C;Hammad H;Didierlaurent AM;Lambrecht BN
佐剂系统AS 01在脂质体制剂中含有单磷酰脂质A（MPL）和皂苷QS-21。AS 01被包括在最近开发的针对疟疾和水痘带状疱疹病毒的疫苗中。与许多其他佐剂一样，AS 01诱导适应性免疫高度依赖于募集和激活树突状细胞（DC）的能力，树突状细胞迁移到引流淋巴结以刺激T和B细胞。本研究的目的是更精确地解决不同的常规（cDC）和单核细胞来源的DC（MC）亚群在AS 01佐剂疫苗免疫后的适应性免疫应答的协调中的贡献。与抗原单独给药相比，MPL和QS-21联合给药AS 01可诱导CD 26 + XCR 1 + cDC 1、CD 26 + CD 172 + cDC 2和最近定义的CCR 2依赖性CD 64表达炎性cDC 2（inf-cDC 2）亚群向引流淋巴结的大量募集，而几乎检测不到CD 26-CD 64 + CD 88 + MC。在疫苗接种后24 h，cDC 2和inf-cDC 2在引发抗原特异性CD 4 + T细胞同时将抗原呈递给CD 8 + T细胞的不同亚群中具有上级优势。白喉毒素（DT）介导的所有DCs在疫苗接种前的耗竭完全消除了适应性免疫应答，而疫苗接种后24 h的耗竭主要影响CD 8 + T细胞应答。缺乏Flt 3或趋化因子受体CCR 2的接种小鼠在inf-cDC 2募集中表现出明显的缺陷，并且未能产生适当的抗体和T细胞应答。因此，AS 01的佐剂活性与cDC 2亚群的有效活化相关，包括新描述的inf-cDC 2。
The Adjuvant System AS01 contains monophosphoryl lipid A (MPL) and the saponin QS-21 in a liposomal formulation. AS01 is included in recently developed vaccines against malaria and varicella zoster virus. Like for many other adjuvants, induction of adaptive immunity by AS01 is highly dependent on the ability to recruit and activate dendritic cells (DCs) that migrate to the draining lymph node for T and B cell stimulation. The objective of this study was to more precisely address the contribution of the different conventional (cDC) and monocyte-derived DC (MC) subsets in the orchestration of the adaptive immune response after immunization with AS01 adjuvanted vaccine. The combination of MPL and QS-21 in AS01 induced strong recruitment of CD26+XCR1+ cDC1s, CD26+CD172+ cDC2s and a recently defined CCR2-dependent CD64-expressing inflammatory cDC2 (inf-cDC2) subset to the draining lymph node compared to antigen alone, while CD26-CD64+CD88+ MCs were barely detectable. At 24 h post-vaccination, cDC2s and inf-cDC2s were superior amongst the different subsets in priming antigen-specific CD4+ T cells, while simultaneously presenting antigen to CD8+ T cells. Diphtheria toxin (DT) mediated depletion of all DCs prior to vaccination completely abolished adaptive immune responses, while depletion 24 h after vaccination mainly affected CD8+ T cell responses. Vaccinated mice lacking Flt3 or the chemokine receptor CCR2 showed a marked deficit in inf-cDC2 recruitment and failed to raise proper antibody and T cell responses. Thus, the adjuvant activity of AS01 is associated with the potent activation of subsets of cDC2s, including the newly described inf-cDC2s.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
30.3
作者：
Hohl TM;Rivera A;Lipuma L;Gallegos A;Shi C;Mack M;Pamer EG
通讯作者：
Pamer EG
影响因子：
64.5
作者：
Binnewies, Mikhail;Mujal, Adriana M.;Krummel, Matthew F.
通讯作者：
Krummel, Matthew F.
影响因子：
32.4
作者：
Groom JR;Richmond J;Murooka TT;Sorensen EW;Sung JH;Bankert K;von Andrian UH;Moon JJ;Mempel TR;Luster AD
通讯作者：
Luster AD
影响因子：
64.5
作者：
DiLillo DJ;Ravetch JV
通讯作者：
Ravetch JV