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      The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity

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          Abstract

          Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called “kynurenines” that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity and the rejection of transplanted tissues. Finally, we examine how vaccines may enhance immune suppression of autoimmunity through the upregulation of IDO biosynthesis in human dendritic cells.

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          GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.

          David Munn, Madhav D. Sharma, Babak Baban … (2005)
          Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
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            Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism.

            Nam Trung Nguyen, Akihiro Kimura, Taisuke Nakahama … (2010)
            Although an immunoregulatory role of aryl hydrocarbon receptor (Ahr) has been demonstrated in T cells and macrophages, little is known about its function in dendritic cells (DC). Here, we show that lipopolysaccharide (LPS) and CpG stimulate Ahr expression in bone marrow-derived dendritic cells (BMDC). Furthermore, we found that Ahr is required to induce indoleamine 2,3-dioxygenase (IDO) expression, an immunosuppressive enzyme that catabolizes tryptophan into kynurenine (Kyn) and other metabolites in DC. In the presence of LPS or CpG, Ahr-deficient (Ahr(-/-)) mature BMDC induced immune responses characterized by reduced Kyn and IL-10 production compared with results observed with tolerogenic mature WT BMDC. In a coculture system with LPS- or CpG-stimulated BMDC and naive T cells, Ahr(-/-) BMDC inhibited naive T-cell differentiation into regulatory T (Treg) cells, which likely facilitated Th17 cell development and promoted naive T-cell proliferation. Addition of synthetic L-Kyn to the coculture system skewed the differentiation of naive T cells to Treg cells rather than Th17 cells. Taken together, our results demonstrate a previously unknown negatively regulatory role for Ahr in DC-mediated immunogenesis in the presence of LPS or CpG, which, in turn, alters the Kyn-dependent generation of Treg cells and Th17 cells from naive T cells.
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              Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.

              Michael Platten, Wolfgang Wick, Benoît van den Eynde (2012)
              Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid cancer, with the aim of enhancing the efficacy of conventional chemotherapy. There are, however, certain tumor types that are capable of catabolizing tryptophan but are largely IDO-negative. Recent evidence from studies in malignant gliomas and other types of cancers points to alternative enzymatic pathways of tryptophan catabolism involving tryptophan-2,3-dioxygenase (TDO). TDO, which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers and is equally capable of suppressing antitumor immune responses. Depletion of tryptophan induces signaling events in T cells, leading to anergy and apoptosis; however, active immunomodulation by accumulating tryptophan catabolites, most notably kynurenine, appears to play an equally important role. These immunomodulatory effects of kynurenine are mediated by the aryl hydrocarbon receptor. This intracellular transcription factor has classically been viewed as a receptor for environmental toxins, such as dioxin, and its important role in influencing immune responses, especially in epithelial barriers, is only beginning to emerge. This review summarizes the exciting developments in our understanding of tryptophan catabolism as a key factor in the immunobiology of cancer. ©2012 AACR.
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                Author and article information

                Contributors
                Diane M. Harper: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Vaccines (Basel)
                Journal ID (iso-abbrev): Vaccines (Basel)
                Journal ID (publisher-id): vaccines
                Title: Vaccines
                Publisher: MDPI
                ISSN (Electronic): 2076-393X
                Publication date (Electronic): 10 September 2015
                Publication date Collection: September 2015
                Volume: 3
                Issue: 3
                Pages: 703-729
                Affiliations
                [1 ]Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; E-Mails: jmbongue@ 123456llu.edu (J.C.M.); dnicholas@ 123456llu.edu (D.A.N.); nkim@ 123456llu.edu (N.-S.K.)
                [2 ]California Baptist University, Riverside, CA 92504, USA; E-Mail: t2torrez722@ 123456gmail.com
                [3 ]Department of Molecular Biology, Chonbuk National University, Jeon-Ju 54896, Korea
                [4 ]Endocrinology Section, JL Pettis Memorial VA Medical Center, Loma Linda, CA 92357, USA; E-Mail: Anthony.firek@ 123456va.gov
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: blangridge@ 123456llu.edu ; Tel.: +1-909-558-1000; Fax: +1-909-558-0177.
                Article
                Publisher ID: vaccines-03-00703
                DOI: 10.3390/vaccines3030703
                PMC ID: 4586474
                PubMed ID: 26378585
                SO-VID: f3b9e6bb-c6c9-4bfb-a18f-b9ee378fe3ee
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 August 2015
                Date accepted : 02 September 2015
                Categories
                Subject: Review

                Keywords: indoleamine 2, 3-dioxygenase,tryptophan,nf-κb,vaccine,ctb-ins
                Data availability:
                Keywords: indoleamine 2, 3-dioxygenase, tryptophan, nf-κb, vaccine, ctb-ins

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