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. 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 potential vaccine adjuvant against viral infection. WT mouse germinal-center B cells (3 replicates) Gla KO mouse germinal-center B cells (3 replicates) A4galt KO mouse germinal-center B cells (3 replicates) WT mouse naive B cells (3 replicates) Gla KO mouse naive B cells (3 replicates) A4galt KO mouse naive B cells (3 replicates)