High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

• DOI: 10.1038/ncomms2874
• Publication Date: 2013-05-14T07:44:41Z
• Authors: Claudia Volpi; Francesca Fallarino; Maria T. Pallotta; Roberta Bianchi; Carmine Vacca; Maria L. Belladonna; Ciriana Orabona; Antonella De Luca; Louis Boon; Luigina Romani; Ursula Grohmann; Paolo Puccetti
• Keywords: TRIF; TLR9; CpG Oligodeoxynucleotide; Toll-Like Receptor 9; CpG site

CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-κB signalling and the induction of IRF3- and TGF-β-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling--was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators.