title: Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes.
abstract: Indoleamine 2,3-dioxygenase (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions. We have recently demonstrated that IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines, but it also acts as a signal-transducing molecule, independently of its enzymic function. IDO1 signalling activity is triggered in plasmacytoid dendritic cells (pDCs) by transforming growth factor-β (TGF-β), an event that requires the non-canonical NF-κB pathway and induces long-lasting IDO1 expression and autocrine TGF-β production in a positive feedback loop, thus sustaining a stably regulatory phenotype in pDCs. IDO1 expression and catalytic function are defective in pDCs from non-obese diabetic (NOD) mice, a prototypic model of autoimmune diabetes. In the present study, we found that TGF-β failed to activate IDO1 signalling function as well as up-regulate IDO1 expression in NOD pDCs. Moreover, TGF-β-treated pDCs failed to exert immunosuppressive properties in vivo. Nevertheless, transfection of NOD pDCs with Ido1 prior to TGF-β treatment resulted in activation of the Ido1 promoter and induction of non-canonical NF-κB and TGF-β, as well as decreased production of the pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α). Overexpression of IDO1 in TGF-β-treated NOD pDCs also resulted in pDC ability to suppress the in vivo presentation of a pancreatic β-cell auto-antigen. Thus, our data suggest that a correction of IDO1 expression may restore its dual function and thus represent a proper therapeutic manoeuvre in this autoimmune setting.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pallotta
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Belladonna
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Giada
authors.initials: G
authors.lastname: Mondanelli
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegrucci
authors.forename: Vincenzo Nicola
authors.initials: VN
authors.lastname: Talesa
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016328:NF-kappa B; D012333:RNA, Messenger; D007737:Kynurenine
keywords: IDO1; autoimmune diabetes; immune regulation; non-canonical NF-κB; non-obese diabetic (NOD) mice; plasmacytoid dendritic cells; tryptophan catabolism