The Th1/Tfh-like biased responses elicited by the rASP-1 innate adjuvant are dependent on TRIF and Type I IFN receptor pathways.
The Th1/Tfh-like biased responses elicited by the rASP-1 innate adjuvant are dependent on TRIF and Type I IFN receptor pathways.
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DOI：
10.3389/fimmu.2022.961094
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
Ov-ASP-1（rASP-1）是一种寄生虫衍生的蛋白质，由蠕虫盘尾丝虫分泌，是一种佐剂，可增强流感三价疫苗（IIV 3）的效力，即使与低40倍的IIV 3一起使用。这项研究的目的是提供一个更深入的了解分子网络，强调佐剂的rASP-1。我们发现rASP-1刺激小鼠CD 11 c+骨髓来源的树突状细胞（BMDCs）分泌IL-12 p40、TNF-α、IP-10和IFN-β水平升高，这是一种TRIF依赖性但不依赖于MyD 88的方式。rASP-1激活的BMDCs促进幼稚CD 4 + T细胞分化为TRIF和I型干扰素受体（IFNAR）依赖的Th 1细胞（IFN-γ+），以及TRIF、MyD 88和IFNAR依赖的Tfh样细胞（IL 21+）和Tfh 1（IFN-γ+ IL 21+）。rASP-1激活的BMDCs仅在MyD 88通路被抑制时促进幼稚CD 4 + T细胞向Th 17（IL-17+）细胞的分化。重要的是，rASP-1活化的人血液cDC表达与DC成熟、I型IFN和II型IFN信号传导以及TLR 4-TRIF依赖性信号传导相关的上调基因。这些活化的cDC促进幼稚人CD 4 + T细胞分化为Th 1、Tfh样和Th 17细胞。因此，我们的数据证实，rASP-1是一种有效的先天性佐剂，极化的适应性T细胞反应的Th 1/Tfh 1在小鼠和人的DC。值得注意的是，rASP-1佐剂化的IIV 3疫苗引起小鼠免受致死性H1N1感染的保护，这也依赖于TLR 4-TRIF轴和IFNAR信号传导途径，以及其诱导抗IIV 3抗体产生的能力。
Ov-ASP-1 (rASP-1), a parasite-derived protein secreted by the helminth Onchocerca volvulus, is an adjuvant which enhances the potency of the influenza trivalent vaccine (IIV3), even when used with 40-fold less IIV3. This study is aimed to provide a deeper insight into the molecular networks that underline the adjuvanticity of rASP-1. Here we show that rASP-1 stimulates mouse CD11c+ bone marrow-derived dendritic (BMDCs) to secrete elevated levels of IL-12p40, TNF-α, IP-10 and IFN-β in a TRIF-dependent but MyD88-independent manner. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th1 cells (IFN-γ+) that was TRIF- and type I interferon receptor (IFNAR)-dependent, and into Tfh-like cells (IL21+) and Tfh1 (IFN-γ+ IL21+) that were TRIF-, MyD88- and IFNAR-dependent. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th17 (IL-17+) cells only when the MyD88 pathway was inhibited. Importantly, rASP-1-activated human blood cDCs expressed upregulated genes that are associated with DC maturation, type I IFN and type II IFN signaling, as well as TLR4-TRIF dependent signaling. These activated cDCs promoted the differentiation of naïve human CD4+ T cells into Th1, Tfh-like and Th17 cells. Our data thus confirms that the rASP-1 is a potent innate adjuvant that polarizes the adaptive T cell responses to Th1/Tfh1 in both mouse and human DCs. Notably, the rASP-1-adjuvanted IIV3 vaccine elicited protection of mice from a lethal H1N1 infection that is also dependent on the TLR4-TRIF axis and IFNAR signaling pathway, as well as on its ability to induce anti-IIV3 antibody production.
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