title: BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway.
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.
authors.affiliation: Institute for immunology and School of Medicine, University of California, Irvine, 92697-4120, USA.
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Thach
authors.initials: T
authors.lastname: Mai
authors.forename: Clayton A
authors.initials: CA
authors.lastname: White
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.forename: John K
authors.initials: JK
authors.lastname: Sakakura
authors.forename: Pina J
authors.initials: PJ
authors.lastname: Patel
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Qahtani
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D051925:CD79 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D019013:CD40 Antigens; D051925:CD79 Antigens; D007074:Immunoglobulin G; D016328:NF-kappa B; D051193:Toll-Like Receptors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase