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

Nat Commun. 2012 Apr 3;3:767. doi: 10.1038/ncomms1769.

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 Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • CD40 Antigens / metabolism
  • CD79 Antigens / genetics
  • CD79 Antigens / metabolism
  • Cells, Cultured
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • Immunoglobulin Class Switching*
  • Immunoglobulin G / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Signal Transduction*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*
  • Up-Regulation*

Substances

  • CD40 Antigens
  • CD79 Antigens
  • Immunoglobulin G
  • NF-kappa B
  • Toll-Like Receptors
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase