Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN Type 1 signaling.
CpG oligodeoxynucleotides (CpG-ODNs) stimulate innate and adaptive immunity by binding to TLR9 molecules. Paradoxically, expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is induced following i.v. CpG-ODN administration to mice. CpG-ODNs induced selective IDO expression by a minor population of splenic CD19+ dendritic cells (DCs) that did not express the plasmacytoid DC marker 120G8. Following CpG-ODN treatment, CD19+ DCs acquired potent IDO-dependent T cell suppressive functions. Signaling through IFN type I receptors was essential for IDO up-regulation, and CpG-ODNs induced selective activation of STAT-1 in CD19+ DCs. Thus, CpG-ODNs delivered systemically at relatively high doses elicited potent T cell regulatory responses by acting on a discrete, minor population of splenic DCs. The ability of CpG-ODNs to induce both stimulatory and regulatory responses offers novel opportunities for using them as immunomodulatory reagents but may complicate therapeutic use of CpG-ODNs to stimulate antitumor immunity in cancer patients.
Mellor
Andrew L
AL
Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, USA.
Baban
Babak
B
Chandler
Phillip R
PR
Manlapat
Anna
A
Kahler
David J
DJ
Munn
David H
DH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis*; D039521:CD11c Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D000276:Adjuvants, Immunologic; D018941:Antigens, CD19; D039521:CD11c Antigen; C408982:CPG-oligonucleotide; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor