BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

Egest J. Pone, Jinsong Zhang, Thach Mai, Clayton A. White, Guideng Li, John K. Sakakura, Pina J. Patel, Ahmed Al-Qahtani, Hong Zan, Zhenming Xu and Paolo Casali ()
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Egest J. Pone: Institute for immunology and School of Medicine, University of California
Jinsong Zhang: Institute for immunology and School of Medicine, University of California
Thach Mai: Institute for immunology and School of Medicine, University of California
Clayton A. White: Institute for immunology and School of Medicine, University of California
Guideng Li: Institute for immunology and School of Medicine, University of California
John K. Sakakura: Institute for immunology and School of Medicine, University of California
Pina J. Patel: Institute for immunology and School of Medicine, University of California
Ahmed Al-Qahtani: Institute for immunology and School of Medicine, University of California
Hong Zan: Institute for immunology and School of Medicine, University of California
Zhenming Xu: Institute for immunology and School of Medicine, University of California
Paolo Casali: Institute for immunology and School of Medicine, University of California

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract By diversifying antibody biological effector functions, class switch DNA recombination has a central role in the maturation of the antibody response. Here we show that BCR-signalling synergizes with Toll-like receptor (TLR) signalling to induce class switch DNA recombination. BCR-signalling activates the non-canonical NF-κB pathway and enhances the TLR-dependent canonical 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 CD79a phosphorylation and Ca2+ mobilization, and activates both the NF-κB pathways to induce AID and class switch DNA recombination in a PI(3)K p85α-dependent fashion. CD40-signalling activates the two NF-κB pathways to induce AID and class switch DNA recombination independent of BCR-signalling. Finally, dual BCR/TLR-engaging NP–lipopolysaccharide effectively elicits class-switched NP-specific IgG3 and IgG2b in mice. Thus, by integrating signals of the non-canonical and canonical NF-κB pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination.

Date: 2012
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DOI: 10.1038/ncomms1769

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