TLR9-mediated signals rescue B-cells from Fas-induced apoptosis via inactivation of caspases

The death receptor, CD95/Fas, serves to eliminate potentially dangerous, self-reactive B cells. Engagement of B-cell receptors (BCR) on mature B-cells mediates the escape from cell death resulting in the activation and expansion of antigen specific clones. In addition to the antigen receptors, the receptors of B-cell activating factor belong to the tumor necrosis factor (TNF) family (BAFFR); moreover, the pattern recognition receptor, TLR9 may also deliver survival signals inhibiting Fas-mediated death of B-cells. Our aim was to compare the mechanism of BCR-induced and the BAFFR- or TLR9-stimulated rescue of B-cells from CD95/Fas-mediated apoptosis. We have found that BAFFR and TLR9 collaborate with BCR to protect B-cells from Fas-induced elimination and the rescue is independent of protein synthesis. The results revealed that the TLR9- and BCR-triggered rescue signals are transmitted through partially overlapping pathways; the protein kinase C (PKC) and the abl kinase induced phosphorylation may inactivate caspases in both CpG and anti-IgG stimulated cells. However, PI3-K activation is crucial upon the BCR driven anti-apoptotic effect, while p38 MAPK-mediated inactivation of caspases seems to play essential role in TLR9-mediated protection against Fas-induced programmed cell death.

► BAFFR and TLR9 mediate fast, autonomous anti-apoptotic signals to A20 B-cells. ► BAFFR and TLR9 stimulated rescue of B-cells are independent of protein synthesis. ► BAFFR and TLR9 collaborate with BCR to protect B-cells from Fas-mediated apoptosis. ► TLR9- and BCR trigger distinct but overlapping pathways to rescue B-cells. ► Inactivation of caspases is crucial in TLR9-mediated survival.