title: Indoleamine 2,3-dioxygenase: from catalyst to signaling function.
abstract: Control of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile regulator of innate and adaptive immune responses. In acute reactions, the otherwise inflammatory cytokine interferon γ (IFN-γ) acts in a feedback fashion to induce IDO's enzymatic function--and thus prevent potentially harmful, exaggerated responses--through the combined effects of tryptophan starvation and tryptophan catabolites acting via the aryl hydrocarbon receptor of T cells. IDO, however, is also involved in the maintenance of stable tolerance to self in noninflammatory contexts, thus restraining autoimmunity. Exposure, indeed, of mouse plasmacytoid DCs (pDCs) to transforming growth factor β (TGF-β) provides IDO with regulatory effects that are distinct, in nature, from its enzymic activity. Once phosphorylated, IDO mediates signaling events culminating in self-amplification and maintenance of a stably regulatory condition in pDCs. Therefore, IDO has dual immunoregulatory functions driven by distinct cytokines. Firstly, the IFN-γ-IDO axis is crucial in generating and sustaining the function of regulatory T cells. Secondly, a nonenzymic function of IDO--as a signaling molecule--contributes to TGF-β-driven tolerance. The latter function is part of a regulatory circuit in pDCs whereby--in response to TGF-β--the kinase Fyn mediates tyrosine phosphorylation of IDO-associated immunoreceptor tyrosine-based inhibitory motifs, resulting in downstream effects that regulate gene expression and preside over a proper, homeostatic balance between immunity and tolerance. All these aspects are covered in this review.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy. fllfnc@tin.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D014364:Tryptophan