title: Physiologic control of IDO competence in splenic dendritic cells.
abstract: Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4→B7 and PD-1→PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.
authors.affiliation: Department of Oral Biology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Chandler
authors.forename: Burles A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.forename: Marlon L
authors.initials: ML
authors.lastname: Sharpe
authors.forename: Loise M
authors.initials: LM
authors.lastname: Francisco
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: C423449:CpG ODN 1826; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9