Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-B activation. Nat. Rev. Immunol. 7, 817-823

Paolo Puccetti and Ursula Grohmann are at the Department of Experimental Medicine, Section of Pharmacology, University of Perugia, Perugia 06126, Italy.
Nature Reviews Immunology (Impact Factor: 34.99). 11/2007; 7(10):817-23. DOI: 10.1038/nri2163
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The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) suppresses T-cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation. 'Reverse signalling' and 'non-canonical activation' of the transcription factor nuclear factor-kappaB (NF-kappaB) characterize the peculiar events that occur in dendritic cells when T-cell-engaged ligands work as signalling receptors and culminate in the induction of IDO expression by dendritic cells in an inhibitor of NF-kappaB (IkappaB) kinase-alpha (IKKalpha)-dependent manner. In this Opinion article, we propose that IDO acts as a bridge between dendritic cells and CD4+ regulatory T cells, and that regulatory T cells use reverse signalling and non-canonical NF-kappaB activation for effector function and self-propagation. This mechanism may also underlie the protective function of glucocorticoids in pathological conditions.

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    • "Important immunomodulatory properties, mainly related to the immunosuppressive effect of IDO, have also been attributed to this pathway [8,9,17]. A feedback mechanism in modulating the immune responses has been proposed because proinflammatory stimuli activate the KP and an anti-inflammatory effect mediated by KYNA has been observed [8,18,19]. "
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    ABSTRACT: Background Bacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT + 401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups. Methods The concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT + 401C/T genotypes. Results In CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-γ and IL-1Ra showed a positive correlation with IDO activity, and TNF-α and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT + 401 C/T variant allele. Conclusion This study suggests a downward modulatory effect of the KP on CSF inflammation during BM.
    Journal of Neuroinflammation 10/2014; 11(1):169. DOI:10.1186/s12974-014-0169-4 · 5.41 Impact Factor
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    • "Overall, on the one hand, pDCs likely present β-cell–auto-antigen–autoantibody complexes to the relevant autoreactive T cells [16]. On the other, pDCs could also be protective, mainly via expression of various molecules fostering tolerance induction, among which is indoleamine 2,3-dioxygenase 1 (IDO1) [17, 18]. "
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    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.
    Journal of Cellular and Molecular Medicine 09/2014; 18(10). DOI:10.1111/jcmm.12360 · 4.01 Impact Factor
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    • "-radical scavenging (2, 10) and later suppression of T-cell responses (11, 12) were discussed. Since many microbial organisms rely on the essential amino acid Trp, its degradation by IDO-expressing cells of the innate immune system was favored as the major IDO-mediated mechanism against infections (13). "
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    ABSTRACT: Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.
    Frontiers in Immunology 08/2014; 5:384. DOI:10.3389/fimmu.2014.00384
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