The lipid Gb3 promotes germinal center B cell responses and anti-viral immunity

Influenza viruses escape immunity due to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. Here, we demonstrate that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 binds and disengages CD19 from its chaperone CD81 for subsequent translocation to the B cell receptor (BCR) complex to trigger signaling. Abundance of Gb3 amplifies the PI3-kinase/Akt/Foxo1 pathway to drive affinity maturation. Moreover, this lipid regulates MHC-II expression to increase diversity of T follicular helper (Tfh) and GC B cells reactive with subdominant epitopes. In influenza infection, Gb3 promotes broadly reactive antibody responses and cross-protection. Thus, we show that Gb3 determines affinity as well as breadth in B cell immunity and propose this lipid as novel vaccine adjuvant against viral infection. One Sentence Summary Gb3 abundance on GC B cells selects antibodies with high affinity and broad epitope reactivities, which are cross-protective against heterologous influenza infection.

流感病毒因快速的抗原进化而逃避免疫，这就需要能引发广泛保护性抗体反应的疫苗接种策略。在此，我们证明生发中心（GC）B细胞上表达的脂质球三糖神经酰胺（Gb3）对高亲和力抗体的产生至关重要。从机制上讲，Gb3将CD19与其伴侣CD81结合并使其脱离，随后转移至B细胞受体（BCR）复合物以触发信号传导。Gb3的大量存在会放大PI3 - 激酶/Akt/Foxo1通路以驱动亲和力成熟。此外，这种脂质调节MHC - II的表达，以增加与次要表位反应的T滤泡辅助细胞（Tfh）和GC B细胞的多样性。在流感感染中，Gb3促进广泛的反应性抗体反应和交叉保护。因此，我们表明Gb3决定了B细胞免疫的亲和力和广度，并提出这种脂质可作为针对病毒感染的新型疫苗佐剂。一句话总结：GC B细胞上的Gb3含量选择具有高亲和力和广泛表位反应性的抗体，这些抗体对异源流感感染具有交叉保护作用。