title: High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Maria T
authors.initials: MT
authors.lastname: Pallotta
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Maria L
authors.initials: ML
authors.lastname: Belladonna
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D056747:Immunomodulation / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012882:Skin Tests; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D053759:Interleukin-23; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C408982:CPG-oligonucleotide; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human