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)
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