Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
Front Immunol. 2021 May 18;12:672143. doi: 10.3389/fimmu.2021.672143. eCollection 2021.
Mice reconstituted with a human immune system (humanized mice) provide a robust model to study human immunology, vaccinology, and human infectious diseases. However, the development and function of B cells in humanized mice is impaired. B cells from humanized mice are immature and are impaired in IgM to IgG isotype switch in response to infection or vaccination. In the present study we report that Toll-like receptor 9 (TLR9) agonist CpG-B combined with CD40-targeting vaccination triggered human B cell immunoglobin class-switch from IgM to IgG B cells in humanized mice. Human B cells from mice vaccinated with CpG-B as adjuvant were more mature in phenotype and produced significant levels of both total IgG and antigen-specific IgG. We found that CpG-B treatment activated human pDCs (plasmacytoid dendritic cells) to induce interferon-alpha (IFN-α)expression in humanized mice. Pre-depletion of human pDC abrogated the adjuvant effect of CpG-B. Our results indicate that TLR9 and CD40-targeting vaccination triggers human B cell maturation and immunoglobulin class-switch in a pDC-dependent manner in humanized mice. The findings also shed light on induction of human IgG antibodies in humanized mouse models.
用人类免疫系统重建的小鼠（人源化小鼠）为研究人类免疫学、疫苗学和人类传染病提供了强大的模型。然而，人源化小鼠中的 B 细胞的发育和功能受损。人源化小鼠的 B 细胞不成熟，并且在感染或接种疫苗时，IgM 向 IgG 同种型转换受到损害。在本研究中，我们报告 TLR9 激动剂 CpG-B 与靶向 CD40 的疫苗接种联合使用可触发人源化小鼠中 B 细胞免疫球蛋白同种型从 IgM 向 IgG 转换。用 CpG-B 作为佐剂接种疫苗的小鼠的人 B 细胞在表型上更加成熟，并产生大量总 IgG 和抗原特异性 IgG。我们发现 CpG-B 处理可激活人 pDC（浆细胞样树突状细胞）在人源化小鼠中诱导干扰素-α（IFN-α）表达。人 pDC 的预先耗竭消除了 CpG-B 的佐剂作用。我们的结果表明，TLR9 和靶向 CD40 的疫苗接种以 pDC 依赖性方式触发人源化小鼠中 B 细胞成熟和免疫球蛋白同种型转换。这些发现还为在人源化小鼠模型中诱导人 IgG 抗体提供了思路。
