Kitagawa Satoki, Matsuda Teppei, Washizaki Ayaka, Murakami Hirotomo, Yamamoto Takuya, Yoshioka Yasuo
Laboratory of Nano-Design for Innovative Drug Development, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Vaccine Creation Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
NPJ Vaccines. 2022 Oct 6;7(1):115. doi: 10.1038/s41541-022-00541-6.
Nucleic acid-based adjuvants such as CpG oligonucleotides (CpG ODNs) and poly(I:C) are potential vaccine adjuvants for infectious diseases and cancers. However, the mechanism by which their cell surface receptors promote their uptake into dendritic cells (DCs) and shuttle them to intracellular Toll-like receptors remains to be further investigated. Here, we demonstrated a role for nucleolin, a multifunctional DNA- and RNA-binding protein and a major constituent of the nucleolus, as one of the cell-surface receptors for nucleic acid-based adjuvants. Nucleolin on mouse DC surface bound directly to A-type CpG ODN, B-type CpG ODN, and poly(I:C) and promoted their internalization into cells following DC maturation in vitro. In human DCs, nucleolin also contributed to the binding and internalization of both types of CpG ODNs and subsequent cytokine production. Furthermore, nucleolin played a crucial role in cytokine production and activating antigen-specific antibodies and T cell responses induced by B-type CpG ODN in vivo in mice. Our findings provide valuable information that can help improve the efficacy and safety of these adjuvants.
基于核酸的佐剂，如CpG寡核苷酸（CpG ODNs）和聚肌胞苷酸（poly(I:C)），是用于传染病和癌症的潜在疫苗佐剂。然而，其细胞表面受体促进它们被树突状细胞（DCs）摄取并将它们转运至细胞内Toll样受体的机制仍有待进一步研究。在此，我们证明了核仁素（一种多功能的DNA和RNA结合蛋白以及核仁的主要成分）作为基于核酸的佐剂的细胞表面受体之一所发挥的作用。小鼠DC表面的核仁素直接结合A型CpG ODN、B型CpG ODN和聚肌胞苷酸，并在体外DC成熟后促进它们内化进入细胞。在人DC中，核仁素也有助于两种类型CpG ODN的结合和内化以及随后的细胞因子产生。此外，核仁素在小鼠体内由B型CpG ODN诱导的细胞因子产生以及激活抗原特异性抗体和T细胞反应中起关键作用。我们的发现提供了有价值的信息，有助于提高这些佐剂的效力和安全性。
