Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells

Abstract

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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Figure 1: IDO catalytic activity is not required for the IDO-dependent, immunoregulatory effects of pDCs conditioned with TGF-β in vitro.
Figure 2: The catalytic activity of IDO is not required for IDO-dependent, immunoregulatory effects induced in vivo by pDCs conditioned with TGF-β.
Figure 3: TGF-β induces the formation of IDO–SHP-1–SHP-2 complexes and activation of SHP-1 phosphatase activity in pDCs.
Figure 4: IDO phosphorylation requires PI(3)K-dependent but Smad-independent TGF-β signaling events and is mediated by Fyn but not Syk.
Figure 5: IDO and SHP proteins drive a signaling pathway in pDCs that involves activation of the noncanonical NF-κB pathway and production of type I interferon.
Figure 6: IDO-dependent immunoregulatory effects of pDCs conditioned with TGF-β are mediated by Fyn, SHP proteins, the noncanonical NF-κB pathway and type I interferon signaling.
Figure 7: TGF-β induces long-term expression of IDO in pDCs, but IFN-γ does not.
Figure 8: Long-term immunoregulatory effects in vivo of pDCs conditioned by TGF-β but not those conditioned by IFN-γ.

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Acknowledgements

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.).

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M.T.P. designed and did experiments; C.O., C.Vo. C.Va., M.L.B., R.B., C.B., M.C. and E.M.C.M. did experiments; G.S., S.B. and M.C.F. contributed to experimental design; L.B. and F.G. provided reagents; F.F. designed experiments and supervised research; P.P. supervised research; and U.G. designed experiments, supervised research and wrote the manuscript.

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Correspondence to Ursula Grohmann.

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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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