BCR-signalling synergizes with TLR-signallingfor induction of AID and immunoglobulinclass-switching through the non-canonicalnF-kappa B pathway

摘要

By diversifying antibody biological effector functions, class switch DnA recombination hasa central role in the maturation of the antibody response. Here we show that BCR-signallingsynergizes with Toll-like receptor (TLR) signalling to induce class switch DnA recombination.BCR-signalling activates the non-canonical nF-kappa B pathway and enhances the TLR-dependentcanonical nF-κB pathway, thereby inducing activation-induced cytidine deaminase (AID),which is critical for class switch DnA recombination. Escherichia coli lipopolysaccharide (LPs)triggers dual TLR4/BCR-signalling and induces hallmarks of BCR-signalling, including CD79aphosphorylation and Ca~(2+) mobilization, and activates both the nF-kappa B pathways to induce AIDand class switch DnA recombination in a PI(3)K p85α-dependent fashion. CD40-signallingactivates the two nF-kappa B pathways to induce AID and class switch DnA recombinationindependent of BCR-signalling. Finally, dual BCR/TLR-engaging nP–lipopolysaccharideeffectively elicits class-switched nP-specific IgG3 and IgG2b in mice. Thus, by integratingsignals of the non-canonical and canonical nF-kapp B pathways, BCR and TLRs synergize to induceAID and T-cell-independent class switch DnA recombination.