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由 rASP-1 先天佐剂引发的 Th1/Tfh 样偏向反应依赖于 TRIF 和 I 型 IFN 受体途径。

The Th1/Tfh-like biased responses elicited by the rASP-1 innate adjuvant are dependent on TRIF and Type I IFN receptor pathways.

机构信息

Laboratory Molecular Parasitology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, United States.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.

出版信息

Front Immunol. 2022 Sep 2;13:961094. doi: 10.3389/fimmu.2022.961094. eCollection 2022.

DOI:10.3389/fimmu.2022.961094
PMID:36119026
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9478378/
Abstract
  • (rASP-1), a parasite-derived protein secreted by the helminth , 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.
摘要

(rASP-1)，一种由寄生虫分泌的蛋白，是一种佐剂，可增强流感三价疫苗（IIV3）的效力，即使使用的 IIV3 量减少 40 倍也是如此。本研究旨在更深入地了解 rASP-1 的佐剂作用所依赖的分子网络。在这里，我们显示 rASP-1 以 TRIF 依赖性但 MyD88 非依赖性的方式刺激小鼠 CD11c 骨髓来源的树突状 (BMDC) 分泌高水平的 IL-12p40、TNF-α、IP-10 和 IFN-β。rASP-1 激活的 BMDC 促进幼稚 CD4 T 细胞分化为依赖 TRIF 和 I 型干扰素受体 (IFNAR) 的 Th1 细胞（IFN-γ），以及依赖 TRIF、MyD88 和 IFNAR 的 Tfh 样细胞（IL21）和 Tfh1（IFN-γ IL21）。rASP-1 激活的 BMDC 仅在抑制 MyD88 途径时促进幼稚 CD4 T 细胞分化为 Th17（IL-17）细胞。重要的是，rASP-1 激活的人血 cDC 表达上调的基因，这些基因与 DC 成熟、I 型和 II 型 IFN 信号以及 TLR4-TRIF 依赖信号有关。这些激活的 cDC 促进幼稚人 CD4 T 细胞分化为 Th1、Tfh 样和 Th17 细胞。因此，我们的数据证实 rASP-1 是一种有效的先天佐剂，可使小鼠和人 DC 中的适应性 T 细胞反应向 Th1/Tfh1 极化。值得注意的是，rASP-1 佐剂的 IIV3 疫苗可保护小鼠免受致命性 H1N1 感染，这也依赖于 TLR4-TRIF 轴和 IFNAR 信号通路，以及其诱导抗 IIV3 抗体产生的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/7283bd269d6d/fimmu-13-961094-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/beba9fe9ec88/fimmu-13-961094-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/96f399ed3a34/fimmu-13-961094-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/bc86e6b39b95/fimmu-13-961094-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/a3a2dfb4736c/fimmu-13-961094-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/fd5dff95f15d/fimmu-13-961094-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/1e437022ba6f/fimmu-13-961094-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/f2f5422a578d/fimmu-13-961094-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/7283bd269d6d/fimmu-13-961094-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/beba9fe9ec88/fimmu-13-961094-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/96f399ed3a34/fimmu-13-961094-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/bc86e6b39b95/fimmu-13-961094-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/a3a2dfb4736c/fimmu-13-961094-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/fd5dff95f15d/fimmu-13-961094-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/1e437022ba6f/fimmu-13-961094-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/f2f5422a578d/fimmu-13-961094-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e36/9478378/7283bd269d6d/fimmu-13-961094-g008.jpg

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