Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake
Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake
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DOI：
10.1126/scitranslmed.aal2094
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发表时间：
2017-06-07
影响因子：
17.1
通讯作者：
Lore, Karin
中科院分区：
文献类型：
--
作者：
Liang, Frank;Lindgren, Gustaf;Lore, Karin
佐剂增强疫苗诱导的适应性免疫效力和保护的先天免疫机制在很大程度上是未知的。我们介绍了一个模型来描述佐剂驱动的先天免疫激活如何导致启动使用恒河猴疫苗反应的步骤。荧光标记的HIV-1包膜糖蛋白（Env）与常规铝盐（明矾）佐剂一起给药。将其与带有预吸收toll样受体7 （TLR7）配体（铝-TLR7）的明矾或乳剂MF59给予的Env进行比较，因为它们在定性和定量上都优于明矾。所有佐剂均诱导免疫细胞快速而强健地浸润到注射部位的肌肉。这导致中性粒细胞、单核细胞、髓细胞和浆细胞样树突状细胞（dc）大量摄取Env，并完全迁移到疫苗引流淋巴结（LNs）。中性粒细胞虽然不如单核细胞和DCs熟练，但能够将Env呈递到记忆CD4(+) T细胞。与明矾相比，MF59和铝- tlr7表现出更明显的细胞激活和总体上更高的Env（+）细胞数量。这导致大量env特异性CD4(+) T细胞在疫苗引流LNs中启动，这与T滤泡辅助细胞分化和生发中心形成的增加直接相关。因此，强大的先天免疫激活促进疫苗抗原有效递送到引流LNs中的浸润抗原呈递细胞是优质佐剂增强疫苗应答的重要机制。
The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4(+) T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env(+) cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4(+) T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses.