Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses.
Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses.
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DOI：
10.1371/journal.ppat.1010255
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Igyártó BZ
中科院分区：
文献类型：
--
作者：
Ndeupen S;Bouteau A;Herbst C;Qin Z;Jacobsen S;Powers NE;Hutchins Z;Kurup D;Diba LZ;Watson M;Ramage H;Igyártó BZ
在许多临床前动物疫苗研究中，核苷修饰的mRNA与Acuitas Therapeutics的脂质纳米颗粒（LNPs）联合已被证明支持强大的体液免疫反应，后来在接种了SARS-CoV-2疫苗的人类中也得到了支持。我们最近发现，由于LNPs的可电离脂质成分，该平台具有高度炎症性。炎症特性是支持强有力的体液免疫反应发展的关键。然而，该平台驱动T滤泡辅助细胞（Tfh）和体液免疫反应的机制尚不清楚。本研究表明，缺乏朗格汉斯细胞或cDC1s不会显著影响PR8 HA和SARS-CoV-2 rbd特异性Tfh细胞的诱导和体液免疫反应，也不会影响对流感和SARS-CoV-2致命挑战的易感性。然而，这两个DC亚群的联合缺失导致PR8 HA和SARS-CoV-2 rbd特异性Tfh细胞和体液免疫反应的诱导显著降低。尽管存在这些观察到的缺陷，这些小鼠仍然免受致命流感和SARS-CoV-2的攻击。我们进一步发现，与中性粒细胞不同，IL-6需要产生正常的Tfh细胞和抗体反应，但不需要保护免受流感攻击。总之，我们提供的证据表明，mRNA-LNP平台可以在缺乏某些先天免疫细胞和细胞因子的情况下支持诱导保护性免疫反应。随着SARS-CoV-2的持续流行，mRNA-LNP疫苗平台受到了广泛关注。每天有数百万人接触这些疫苗，但其驱动抗体反应和副作用的免疫机制仍未被探索。因此，我们在流感和SARS-CoV-2感染的小鼠模型中测试了该疫苗平台，这些模型缺乏已知在诱导抗体反应中起作用的特异性先天免疫细胞或细胞因子。我们发现，抗原呈递的先天免疫细胞和一种炎症细胞因子的联合缺失显著抑制了由该平台引发的适应性免疫细胞反应。然而，尽管存在观察到的缺陷，mRNA-LNP疫苗驱动的免疫反应仍然能够保护动物免受致命流感或SARS-CoV-2的攻击。这种高度的冗余可能与该平台的高度炎症性有关。
Nucleoside modified mRNA combined with Acuitas Therapeutics’ lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs’ ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, these mice remained protected from lethal influenza and SARS-CoV-2 challenges. We further found that IL-6, unlike neutrophils, was required to generate normal Tfh cells and antibody responses, but not for protection from influenza challenge. In summary, here we bring evidence that the mRNA-LNP platform can support the induction of protective immune responses in the absence of certain innate immune cells and cytokines. The mRNA-LNP vaccine platform has gained much attention with the ongoing SARS-CoV-2 pandemic. Millions of people are exposed to these vaccines daily, but their immune mechanism driving the antibody responses and side effects remains unexplored. Therefore, we tested this vaccine platform in the context of influenza and SARS-CoV-2 infections in mouse models that lack specific innate immune cells or cytokines known to play a role in inducing antibody responses. We show that the combined deletion of antigen-presenting innate immune cells and one of the inflammatory cytokines significantly inhibited adaptive immune cell responses triggered by this platform. However, despite the observed defects, the immune responses driven by the mRNA-LNP vaccine were still able to protect the animals from lethal influenza or SARS-CoV-2 challenges. This high degree of redundancy might be associated with the highly inflammatory nature of this platform.
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影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
6
作者：
Campana P;Parisi V;Leosco D;Bencivenga D;Della Ragione F;Borriello A
通讯作者：
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影响因子：
10.6
作者：
Downs KP;Nguyen H;Dorfleutner A;Stehlik C
通讯作者：
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影响因子：
24.8
作者：
Krishnaswamy JK;Gowthaman U;Zhang B;Mattsson J;Szeponik L;Liu D;Wu R;White T;Calabro S;Xu L;Collet MA;Yurieva M;Alsén S;Fogelstrand P;Walter A;Heath WR;Mueller SN;Yrlid U;Williams A;Eisenbarth SC
通讯作者：
Eisenbarth SC
影响因子：
20.3
作者：
Eddahri, Fouad;Denanglaire, Sebastien;Andris, Fabienne
通讯作者：
Andris, Fabienne