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2,3-Dioxygenase Indoleamine the Immunomodulatory Enzyme Amino Acid Deprivation Links BLIMP-1 To

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2,3-Dioxygenase Indoleamine the Immunomodulatory Enzyme Amino Acid Deprivation Links BLIMP-1 To Amino Acid Deprivation Links BLIMP-1 to the Immunomodulatory Enzyme Indoleamine 2,3-Dioxygenase This information is current as Nicholas A. Barnes, Sophie J. Stephenson, Reuben M. Tooze of September 29, 2021. and Gina M. Doody J Immunol 2009; 183:5768-5777; Prepublished online 14 October 2009; doi: 10.4049/jimmunol.0803480 http://www.jimmunol.org/content/183/9/5768 Downloaded from References This article cites 58 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/183/9/5768.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Amino Acid Deprivation Links BLIMP-1 to the Immunomodulatory Enzyme Indoleamine 2,3-Dioxygenase1 Nicholas A. Barnes, Sophie J. Stephenson, Reuben M. Tooze, and Gina M. Doody2 Catabolism of tryptophan by IDO1 plays an important role in the control of immune responses. Activation of the eukaryotic initiation factor 2␣ (eIF2␣) kinase general control nonderepressible-2 (GCN2) following tryptophan depletion is a major pathway mediating this effect. However, immunomodulatory target genes of GCN2 activation are poorly defined. The transcriptional repressor B lymphocyte-induced maturation protein-1 (BLIMP-1) is a target of the eIF2␣ kinase1, protein kinase-like ER kinase (PERK) during the unfolded protein response of the endoplasmic reticulum. Thus, BLIMP-1 might also be a mediator of the GCN2 stress response pathway activated by IDO1 and tryptophan depletion. Indeed, in human monocytes BLIMP-1 mRNA and protein are up-regulated in response to both a pharmacological activator of GCN2 and tryptophan-depletion generated by IDO1-trans- fected cells. This suggests a functional role for BLIMP-1 in the immunomodulatory effects of the IDO1-GCN2 axis. BLIMP-1 has Downloaded from been shown to repress IFN-␥-regulated promoters. As IDO1 is itself highly responsive to IFN-␥, we hypothesized that BLIMP-1 functions in a feedback loop to regulate IDO1 expression. We found that BLIMP-1 binds to IFN-responsive sites in the IDO1 promoter and represses IFN-dependent IDO1 activation. We propose that BLIMP-1 acts in a negative feedback loop to success- fully balance the outcome of tolerance vs inflammation. The Journal of Immunology, 2009, 183: 5768–5777. he metabolic enzyme IDO1 contributes to the balance be- that accumulate during cellular starvation (14, 15). The sole iden- http://www.jimmunol.org/ tween tolerance vs inflammation in a number of experi- tified target of GCN2 is the translation initiation factor, eukaryotic T mental models. Expression of IDO1 in APCs, such as initiation factor 2␣ (eIF2␣) (16). Phosphorylation of eIF2␣ medi- macrophages and dendritic cells, can suppress T cell responses as ates inhibition of global protein synthesis, but paradoxically in- observed during mammalian pregnancy, inflammatory conditions, creases the translation of activating transcription factor 4 (13, 17). autoimmunity, and tumor resistance (1–6). IDO1 is itself modu- Activating transcription factor 4, along with other selected tran- lated in the presence of inflammatory stimuli, exhibiting strong scriptional regulators, then activates the genetic program required induction in response to both IFN and TLR signaling (7, 8). This to achieve cellular homeostasis (18). enzyme catabolizes the essential amino acid tryptophan, thus de- The importance of GCN2 during the T cell response to trypto- creasing concentrations in the local microenvironment as well as phan depletion has been established. T cells from GCN2-deficient by guest on September 29, 2021 generating biologically active downstream metabolites (9, 10). mice are refractory to IDO1-mediated suppression of proliferation While either of these pathways may operate to regulate T cells, the in vitro and induction of anergy in vivo (19). There is also accu- existing evidence suggests that both mechanisms are required to mulating evidence that GCN2 activation plays a role in the IDO1- achieve the optimal effect (11). expressing APCs themselves. For example, a recent report dem- The ability to sense and respond to decreasing concentrations of onstrated that IDO1 and GCN2 regulate autocrine IFN-␣-driven amino acids is an important cellular survival mechanism, and the amplification of IDO1 expression in plasmacytoid dendritic cells pathways that mediate this effect are well conserved. Studies in (20). GCN2 belongs to a family of kinases that phosphorylate both yeast and mice revealed that the protein kinase general con- eIF2␣ in response to diverse forms of cellular stress (21). Heme- trol nonderepressible-2 (GCN2)3 plays a central role in the re- regulated inhibitor (HRI) is activated by oxidative stress and he- sponse to amino acid deprivation (12, 13). This kinase undergoes moglobin levels during erythrocyte maturation, protein kinase R a change in activation status upon binding to uncharged tRNAs by dsRNA, and the endoplasmic reticulum (ER) resident homolog of protein kinase R, protein kinase-like ER kinase (PERK), is ac- tivated during the unfolded protein response (22–24). We have Section of Experimental Haematology, Leeds Institute of Molecular Medicine, St previously shown that pharmacological activators of PERK up- James’s University Hospital, Leeds, United Kingdom regulate B lymphocyte-induced maturation protein-1 (BLIMP-1) Received for publication October 15, 2008. Accepted for publication August 31, in cells of the myeloid lineage (25). Furthermore, BLIMP-1 was 2009. originally identified as a postinduction transcriptional repressor of The costs of publication of this article were defrayed in part by the payment of page IFN-␤ in response to intracellular dsRNA accompanying viral in- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. fection (26, 27). These data suggest that BLIMP-1 may be a com- 1 This work was supported by a New Investigator Grant (BB/E000746/1) from the mon target of stress-induced signaling pathways. In turn, the in- U.K. Biotechnology and Biological Sciences Research Council (to G.M.D.). duction of BLIMP-1 may shape the outcome of the integrated 2 Address correspondence and reprint requests to Dr. Gina M. Doody, Section of stress response by altering gene expression. Experimental Haematology, Wellcome Trust Brenner Building, Leeds Institute of BLIMP-1 is a Kru¨ppel-type zinc-finger protein that exhibits Molecular Medicine, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, United Kingdom. E-mail address: [email protected] preferential binding to sequences with a high degree of overlap 3 Abbreviations used in this paper: GCN2, general control nonderepressible-2; eIF2␣, eukaryotic initiation factor 2␣; HRI, heme-regulated inhibitor; ER, endoplasmic re- homologous protein; XBP-1, X-box binding protein 1; ISRE, IFN-stimulated re- ticulum; PERK, protein kinase-like ER kinase; BLIMP-1, B lymphocyte-induced sponse element; ChIP, chromatin immunoprecipitation. maturation protein-1; IRF-E, IFN regulatory factor-element; IRF, IFN regulatory fac- tor; FL, full length; siRNA, small interfering RNA; wt, wild type; CHOP, C/EBP Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803480 The Journal of Immunology 5769 with the IFN regulatory factor-element (IRF-E) found in promoters ates were also analyzed using an in-line RF 2000 fluorescence detector responsive to IFN-␥ (28, 29). Work from our laboratory has shown with 280 and 340 nm excitation and emission wavelengths. Fluorescence that BLIMP-1 is indeed capable of repressing genes regulated by detector gain settings were chosen to give more sensitive detection of tryp- ␥ tophan in more dilute samples than was possible using UV absorbance. IFN- (30, 31). In these examples, BLIMP-1 mediates repression Concentrations of tryptophan in media samples were determined from a through direct competition with IFN regulatory factors (IRFs) at calibration curve based on the peak area (calculated using Dionex Chrome- the IRF-E sites contained within their promoters. However, leon software) for absorbance at 278 nm or the fluorescence emission at BLIMP-1 can also exert its repressive effect through the recruit- 340 nm depending on the concentration. ment of histone-modifying enzymes (27, 32–35). Thus, BLIMP-1 RT-PCR has the potential to either transiently repress its targets or to alter- natively ensure stable epigenetic silencing. RNA was isolated by the TRIzol method (Invitrogen) and subjected to DNase ␥ I treatment (DNA-free; Ambion). cDNA was generated using oligo(dT) and The IDO1 promoter is highly responsive to IFN- and is rapidly SuperScript
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