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 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.

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

“…However, whether HMGB1 plays a role in autoantibody produc- (14)(15)(16). BCR could enhance the TLR-dependent canonical NF-kB pathway, likely through TRAF6 activation, and TLR could enhance the BCR-activated noncanonical NF-kB pathway by inducing p100 expression, thereby synergizing to cause activation-induced cytidine deaminase and class-switch DNA recombination (56). Meanwhile, HMGB1, which is a component of circulating DNA-containing ICs, could activate the TLR2/ MyD88/miR-155 pathway and, thus, decrease Ets-1 expression, which contributes to plasmacytic differentiation by upregulating the activity of Blimp-1.…”

“…Previous studies showed that DNA-containing ICs could induce the activation and proliferation of autoreactive B cells through BCR and TLR9 (14)(15)(16). A recent study showed that BCR signaling activated the noncanonical NF-kB pathway and enhanced the TLR-dependent canonical NF-kB pathway, resulting in activation-induced cytidine deaminase, which is critical for class-switch DNA recombination (56). In this study, we demonstrated that HMGB1, which is a component of circulating DNA-containing ICs, could activate the TLR2/MyD88/miR-155 pathway and, thus, decrease Ets-1 expression.…”

The B-cell antigen receptor integrates adaptive and innate immune signals

“…Quite fittingly, the work of Pone et al has identified an interplay between BCR and TLR signaling in the control of class-switch recombination in the activated B cells. This was mediated by NF-κB signals downstream of both receptors, which, significantly, depended on PI-3K activity in the case of the BCR (8).…”

“…Indeed, early experiments addressing the in vitro response of mouse B cells to bacterial lipopolysaccharide (LPS) have suggested cooperation of LPS stimulation and BCR engagement in the proliferative B-cell response under certain conditions (6,7). More recent work has uncovered a synergy between TLR and BCR in the control of class-switch recombination in activated B cells (8), and the role of the BCR in the delivery of DNA-or RNA-associated autoantigens to endosomal TLRs in autoimmunity is well established (9). How B cells integrate signals from the BCR and from coreceptors responding to mitogenic stimuli in the induction of the proliferative response is unclear, however.…”

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

“…Engagement of TLR4 by lipopolysaccharide (LPS), for example, has been shown to affect many aspects of B-cell activity, including cell proliferation, Ig-class switch, plasma-cell differentiation and antibody production as well as their antigen-presenting capacity. 11,12 In contrast, limited information is currently available regarding the potential role of TLR4-mediated signaling in early B-cell development. In one report, LPS was shown to exert an inhibitory effect on B lymphopoiesis by promoting myeloid differentiation of hematopoietic progenitors through a Myd88-dependent mechanism.…”