Physiologic control of IDO competence in splenic dendritic cells

Babak Baban, Phillip R. Chandler, Burles A. Johnson, Lei Huang, Minghui Li, Marlon L. Sharpe, Loise M. Francisco, Arlene H. Sharpe, Bruce R. Blazar, David H. Munn, Andrew L. Mellor

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59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2329-2335
Number of pages7
JournalJournal of Immunology
Volume187
Issue number5
DOIs
StatePublished - Sep 1 2011

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    Baban, B., Chandler, P. R., Johnson, B. A., Huang, L., Li, M., Sharpe, M. L., Francisco, L. M., Sharpe, A. H., Blazar, B. R., Munn, D. H., & Mellor, A. L. (2011). Physiologic control of IDO competence in splenic dendritic cells. Journal of Immunology, 187(5), 2329-2335. https://doi.org/10.4049/jimmunol.1100276