A goal of immunization against highly mutable viruses is to elicit broadly neutralizing antibody responses. In Science, Sharma et al. report that the glycosphingolipid globotriaosylceramide (Gb3, also known as CD77) increases antibody affinity and diversity after immunization in a mouse model of influenza. Gb3 is highly expressed on germinal center B cells, where its abundance is regulated by α1,4-galactose modification. Genetic modulation to increase α1,4-galactosylation of Gb3 enhanced germinal center responses and antigen-specific production of IgG, particularly isotype IgG2c, in their model system. Importantly, exogenous Gb3 also enhanced germinal center B cell-derived antibody responses after immunization but did not increase extrafollicular B cell responses. Mechanistically, Gb3 facilitates the release of CD19 from the tetraspanin CD81 within the plasma membrane; CD19 then associates with antigen-engaged B cell receptors (BCRs) and promotes phosphorylation and activation of the downstream kinase AKT. Phosphorylated AKT subsequently inactivates the FOXO1 transcription factor and thereby downregulates CXCR4, which regulates spatial positioning of germinal center B cells within the dark zone. The enhanced Gb3–CD19–BCR interaction results in an increase in B cell interactions with follicular T helper cells in the light zones, leading to the increased T cell-dependent antibody responses, including those directed against subdominant epitopes. Finally, the authors show that immunization with Gb3 adjuvants promotes the generation of broadly protective antibodies against heterologous influenza virus strains, which suggests that Gb3-enhanced diversification of antibody responses might prove beneficial against rapidly evolving viral pathogens.

Original reference: Science 383, eadg0564 (2024)

针对高度变异病毒的免疫的一个目标是引发广泛的中和抗体反应。在《科学》中，夏尔马等人。报道称，在流感小鼠模型中免疫后，鞘糖脂三酰神经酰胺（Gb3，也称为 CD77）增加了抗体亲和力和多样性。 Gb3 在生发中心 B 细胞上高度表达，其丰度受 α1,4-半乳糖修饰调节。在他们的模型系统中，通过基因调节来增加 Gb3 的 α1,4-半乳糖基化，增强了生发中心反应和 IgG（特别是同种型 IgG2c）的抗原特异性产生。重要的是，外源性 Gb3 还能增强免疫后生发中心 B 细胞衍生的抗体反应，但不会增加滤泡外 B 细胞反应。从机制上讲，Gb3 促进质膜内的四跨膜蛋白 CD81 释放 CD19；然后 CD19 与抗原结合的 B 细胞受体 (BCR) 结合，促进下游激酶 AKT 的磷酸化和激活。磷酸化的 AKT 随后使 FOXO1 转录因子失活，从而下调 CXCR4，CXCR4 调节暗区内生发中心 B 细胞的空间定位。 Gb3-CD19-BCR 相互作用的增强导致 B 细胞与浅区滤泡 T 辅助细胞的相互作用增加，从而导致 T 细胞依赖性抗体反应增加，包括针对次优势表位的抗体反应。最后，作者表明，Gb3 佐剂免疫促进了针对异源流感病毒株的广泛保护性抗体的产生，这表明 Gb3 增强的抗体反应多样化可能对对抗快速进化的病毒病原体有益。

原始参考： Science 383，eadg0564 (2024)