title: Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO.
abstract: CpG-rich oligonucleotides (CpG-ODN) bind to Toll-like receptor 9 (TLR9) and are used as powerful adjuvants for vaccination. Here we report that CpG-ODN not only act as immune stimulatory agents but can also induce strong immune suppression depending on the anatomical location of application. In agreement with the adjuvant effect, subcutaneous application of antigen plus CpG-ODN resulted in antigen-specific T cell activation in local lymph nodes. In contrast, systemic application of CpG-ODN resulted in suppression of T cell expansion and CTL activity in the spleen. The suppressive effect was mediated by indoleamine 2,3-dioxygenase (IDO) as indicated by the observation that CpG-ODN induced IDO in the spleen and that T cell suppression could be abrogated by 1-methyl-tryptophan (1-MT), an inhibitor of IDO. No expression of IDO was observed in lymph nodes after injection of CpG-ODN, explaining why suppression was restricted to the spleen. Studies with a set of knockout mice demonstrated that the CpG-ODN-induced immune suppression is dependent on TLR9 stimulation and independent of type I and type II interferons. The present study shows that for the use of CpG-ODN as an adjuvant in vaccines, the route of application is crucial and needs to be considered. In addition, the results indicate that down-modulation of immune responses by CpG-ODN may be possible in certain pathological conditions.
authors.affiliation: Institut für Molekulare Medizin und Experimentelle Immunologie, Bonn, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wingender
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Beatrix
authors.initials: B
authors.lastname: Schumak
authors.forename: Frank
authors.initials: F
authors.lastname: Jüngerkes
authors.forename: Elmar
authors.initials: E
authors.lastname: Endl
authors.forename: Dagmar
authors.initials: D
authors.lastname: von Bubnoff
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.forename: Jörg
authors.initials: J
authors.lastname: Striegler
authors.forename: Gerd
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Huster
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D003602:Cytotoxicity, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D010047:Ovalbumin