Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.
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We thank G.C. Prendergast (Lankenau Institute for Medical Research) for the mIDOprom900-luc plasmid, and G. Andrielli for digital art and image editing. Supported by the Italian Ministry of Health (GR-2008-1138004 ('Innovative IDO-targeting interventions in autoimmunity') to C.O.), the Associazione per l'Aiuto ai Giovani con Diabete dell'Umbria (U.G.) and Associazione Italiana per la Ricerca sul Cancro (P.P.).
The authors declare no competing financial interests.
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Pallotta, M., Orabona, C., Volpi, C. et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 12, 870–878 (2011). https://doi.org/10.1038/ni.2077
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