title: Distinct roles of immunoreceptor tyrosine-based motifs in immunosuppressive indoleamine 2,3-dioxygenase 1.
abstract: The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the initial, rate-limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1-dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine-based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP-1 and SHP-2), and thus trigger an immunoregulatory signalling in DCs. This mechanism leads to sustained IDO1 expression, in a feedforward loop, which is particularly important in restraining autoimmunity and chronic inflammation. Yet, under specific conditions requiring that early and protective inflammation be unrelieved, tyrosine-phosphorylated ITIMs will instead bind the suppressor of cytokine signalling 3 (SOCS3), which drives IDO1 proteasomal degradation and shortens the enzyme half-life. To dissect any differential roles of the two IDO1's ITIMs, we generated protein mutants by replacing one or both ITIM-associated tyrosines with phospho-mimicking glutamic acid residues. Although all mutants lost their enzymic activity, the ITIM1 - but not ITIM2 mutant - did bind SHPs and conferred immunosuppressive effects on DCs, making cells capable of restraining an antigen-specific response in vivo. Conversely, the ITIM2 mutant would preferentially bind SOCS3, and IDO1's degradation was accelerated. Thus, it is the selective phosphorylation of either ITIM that controls the duration of IDO1 expression and function, in that it dictates whether enhanced tolerogenic signalling or shutdown of IDO1-dependent events will occur in a local microenvironment.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Albini
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Rosini
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Mondanelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Belladonna
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006207:Half-Life; D007108:Immune Tolerance / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D007737:Kynurenine / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000276:immunology; D000072417:Protein Domains / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology; D014364:Tryptophan / Q000276:immunology; D014443:Tyrosine / Q000276:immunology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050826:Suppressor of Cytokine Signaling Proteins; D007737:Kynurenine; D014443:Tyrosine; D014364:Tryptophan
keywords: IDO1; immunoreceptor tyrosine-based inhibitory motifs (ITIMs); immunosuppression; non-canonical NF-κB; phosphotyrosine; plasmacytoid dendritic cell; proteasome; protein phosphorylation; tyrosine phosphatase