Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO.
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.
Wingender
Gerhard
G
Institut für Molekulare Medizin und Experimentelle Immunologie, Bonn, Germany.
Garbi
Natalio
N
Schumak
Beatrix
B
Jüngerkes
Frank
F
Endl
Elmar
E
von Bubnoff
Dagmar
D
Steitz
Julia
J
Striegler
Jörg
J
Moldenhauer
Gerd
G
Tüting
Thomas
T
Heit
Antje
A
Huster
Katharina M
KM
Takikawa
Osamu
O
Akira
Shizuo
S
Busch
Dirk H
DH
Wagner
Hermann
H
Hämmerling
Günter J
GJ
Knolle
Percy A
PA
Limmer
Andreas
A
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
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