Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Division of Infectious Disease Vaccine Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Osong, Republic of Korea.
Nat Commun. 2024 Aug 27;15(1):7226. doi: 10.1038/s41467-024-51411-9.
mRNA vaccines against SARS-CoV-2 have revolutionized vaccine development, but their immunological mechanisms are not fully understood. Here, we investigate injection site responses of mRNA vaccines by generating a comprehensive single-cell transcriptome profile upon lipid nanoparticle (LNP) or LNP-mRNA challenge in female BALB/c mice. We show that LNP-induced stromal pro-inflammatory responses and mRNA-elicited type I interferon responses dominate the initial injection site responses. By tracking the fate of delivered mRNA, we discover that injection site fibroblasts are highly enriched with the delivered mRNA and that they express IFN-β specifically in response to the mRNA component, not to the LNP component of mRNA vaccines. Moreover, the mRNA-LNP, but not LNP alone, induces migratory dendritic cells highly expressing IFN-stimulated genes (mDC_ISGs) at the injection site and draining lymph nodes. When co-injected with LNP-subunit vaccine, IFN-β induces mDC_ISGs at the injection site, and importantly, it substantially enhances antigen-specific cellular immune responses. Furthermore, blocking IFN-β signaling at the injection site significantly decreases mRNA vaccine-induced cellular immune responses. Collectively, these data highlight the importance of injection site fibroblasts and IFN-β signaling during early immune responses against the mRNA vaccine and provide detailed information on the initial chain of immune reactions elicited by mRNA vaccine injection.
mRNA 疫苗在对抗 SARS-CoV-2 方面取得了革命性的进展，但它们的免疫机制仍不完全清楚。在这里，我们通过在雌性 BALB/c 小鼠中用脂质纳米颗粒（LNP）或 LNP-mRNA 进行挑战，生成综合的单细胞转录组图谱，研究了 mRNA 疫苗的注射部位反应。我们发现，LNP 诱导的基质前炎症反应和 mRNA 引发的 I 型干扰素反应主导了最初的注射部位反应。通过跟踪递送到的 mRNA 的命运，我们发现注射部位成纤维细胞高度富含递送到的 mRNA，并且它们特异性地表达 IFN-β，而不是对 mRNA 疫苗的 LNP 成分作出反应。此外，mRNA-LNP，而不是 LNP 本身，在注射部位和引流淋巴结中诱导高度表达 IFN 刺激基因（mDC_ISGs）的迁移树突状细胞。当与 LNP 亚单位疫苗共同注射时，IFN-β 在注射部位诱导 mDC_ISGs，并且重要的是，它大大增强了抗原特异性细胞免疫反应。此外，在注射部位阻断 IFN-β 信号会显著降低 mRNA 疫苗诱导的细胞免疫反应。总之，这些数据突出了注射部位成纤维细胞和 IFN-β 信号在针对 mRNA 疫苗的早期免疫反应中的重要性，并提供了有关 mRNA 疫苗注射引发的初始免疫反应链的详细信息。
