Abstract
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and of Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions, and was associated with the activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AA:
-
anthranilic acid
- DC:
-
dendritic cell(s)
- 3-HAA:
-
3-hydroxyanthranilic acid
- 3-HK:
-
3-hydroxykynurenine
- IDO:
-
indoleamine 2,3-dioxygenase
- KYN:
-
L-kynurenine
- PI:
-
propidium iodide
- QUIN:
-
quinolinic acid
References
Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL . 1998 Prevention of allogeneic fetal rejection by tryptophan catabolism Science 281: 1191–1193
Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, Munn DH . 2001 Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy Nature Immunol. 2: 64–68
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL . 1999 Inhibition of T cell proliferation by macrophage tryptophan catabolism J. Exp. Med. 189: 1363–1372
Mellor AL, Munn DH . 1999 Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today 20: 469–473
Grohmann U, Bianchi R, Belladonna ML, Silla S, Fallarino F, Fioretti MC, Puccetti P . 2000 IFN-γ inhibits presentation of a tumor/self peptide by CD8α− dendritic cells via potentiation of the CD8α+ subset J. Immunol. 165: 1357–1363
Grohmann U, Fallarino F, Bianchi R, Belladonna ML, Vacca C, Orabona C, Uyttenhove C, Fioretti MC, Puccetti P . 2001 IL-6 inhibits the tolerogenic function of CD8α+ dendritic cells expressing indoleamine 2,3-dioxygenase J. Immunol. 167: 708–714
Fallarino F, Vacca C, Orabona C, Belladonna ML, Bianchi R, Marshall B, Kerskin DB, Mellor AL, Fioretti MC, Grohmann U, Puccetti P . 2002 Functional expression of indoleamine 2,3-dioxygenase by murine CD8α+ dendritic cells Int. Immunol. 14: 65–68
Grohmann U, Puccetti P . 2002 The immunosuppressive activity of proinflammatory cytokines in experimental models: potential for therapeutic intervention in autoimmunity Curr. Drug Targets (Inflammation & Allergy) 1: 77–87
Grohmann U, Fallarino F, Silla S, Bianchi R, Belladonna ML, Vacca C, Micheletti A, Fioretti MC, Puccetti P . 2001 CD40 ligation ablates the tolerogenic potential of lymphoid dendritic cells J. Immunol. 166: 277–283
Shimizu T, Nomiyama S, Hirata F, Hayaishi O . 1978 Indoleamine 2,3-dioxygenase: purification and some properties J. Biol. Chem. 253: 4700–4706
Werner ER, Bitterlich G, Fuchs D, Hausen A, Reibnegger G, Szabo G, Dierich MP, Wachter H . 1987 Human macrophages degrade tryptophan upon induction by interferon-γ Life Sci. 41: 273280
Carlin JM, Borden EC, Sondel PM, Byrne GI . 1989 Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes J. Leukoc. Biol. 45: 29–34
Taylor MW, Feng G . 1991 Relationship between interferon-γ, indoleamine 2,3-dioxygenase, and tryptophan catabolism FASEB J. 5: 2516–2522
Schwarcz R, Whetsell WO, Mangano RM . 1983 Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain Science 219: 316–318
Stone TW . 1993 Neuropharmacology of quinolinic and kynurenic acids Pharmacol. Rev. 45: 309–379
Okuda S, Nishiyama N, Saito H, Katsuki H . 1998 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and regional selectivity J. Neurochem. 70: 299–307
Wei H, Leeds P, Chen RW, Wei W, Leng Y, Bredesen DE, Chuang DM . 2000 Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: characterization and protection by dantrolene and Bcl-2 overexpression J. Neurochem. 75: 81–90
Chiarugi A, Meli E, Moroni F . 2001 Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid J. Neurochem. 77: 1310–1318
Morita T, Saito K, Takemura M, Maekawa N, Fujigaki S, Fujii H, Wada H, Takeuchi S, Noma A, Seishima M . 2001 3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma Ann. Clin. Biochem. 38: 242–251
Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, Sato T, Reed JC, Green D, Swain SL . 1997 Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis J. Exp. Med. 185: 1837–1849
Varadhachary A, Perdow S, Hu C, Ramanarayanan M, Salgame P . 1997 Differential ability of T cell subsets to undergo activation-induced cell death Proc. Natl. Acad. Sci. USA 94: 5778–5783
Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH . 1994 Differential ability of Th1 and Th2 cells to express Fas ligand and to undergo activation-induced cell death Int. Immunol. 6: 1545–1553
Yahata T, Abe N, Yahata C, Ohmi Y, Ohta A, Iwakabe K, Habu S, Yagita H, Kitamura H, Matsuki N, Nakui M, Sato M, Nishimura T . 1999 The essential role of phorbol ester-sensitive protein kinase C isoforms in activation-induced cell death of Th1 cells Eur. J. Immunol. 29: 727–732
Varadhachary AS, Peter ME, Perdow SN, Krammer PH, Salgame P . 1999 Selective up-regulation of phosphatidylinositol 3′-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: a mechanism for Th2 resistance from Fas-mediated apoptosis J. Immunol. 163: 4772–4779
Budd RC . 2001 Activation-induced cell death Curr. Opin. Immunol. 13: 356–362
Leist M, Jaattela M . 2001 Four deaths and a funeral: from caspases to alternative mechanisms Nat. Rev. Mol. Cell. Biol. 2: 589–598
Liu X, Kim CN, Yang J, Jemmerson R, Wang X . 1996 Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c Cell 86: 147–157
Li F, Srinivasan A, Wang Y, Armstrong RC, Tomaselli KJ, Fritz LC . 1997 Cell-specific induction of apoptosis by microinjection of cytochrome c. Bcl-xL has activity independent of cytochrome c release J. Biol. Chem. 272: 30299–30305
Gibson EM, Henson ES, Villanueva J, Gibson SB . 2002 MEK kynase 1 induces mitochondrial permeability transition leading to apoptosis independent of cytochrome c release J. Biol. Chem. 277: 10573–10580
Foster AC, Miller LP, Oldendorf WH, Schwarcz R . 1984 Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat Exp. Neurol. 84: 428–440
Cohen JJ . 1992 Glucocorticoid-induced apoptosis in the thymus Semin. Immunol. 4: 363–369
Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN . 1999 Nuclear factor κB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum J. Neurosci. 19: 4023–4033
Skerry TM, Genever PG . 2001 Glutamate signalling in non-neuronal tissues Trends Pharmacol. Sci. 22: 174–181
Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP . 1998 Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells J. Clin. Invest. 102: 322–328
Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA . 2000 Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation J. Immunol. 164: 3596–3599
Nunez G, Benedict MA, Hu Y, Inohara N . 1998 Caspases: the proteases of the apoptotic pathway Oncogene 17: 3237–3245
Budihardjo I, Oliver H, Lutter M, Luo X, Wang X . 1999 Biochemical pathways of caspase activation during apoptosis Annu. Rev. Cell Dev. Biol. 15: 269–290
Roy S, Nicholson DW . 2000 Cross-talk in cell death signaling J. Exp. Med. 192: F21–F25
Friesen C, Herr I, Krammer PH, Debatin KM . 1996 Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells Nat. Med. 2: 574–577
Müller M, Strand S, Hugh H, Heinemann E-M, Walczak H, Hofmann WJ, Stremmel W, Krammer PH, Galle PR . 1997 Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (Apo-1/Fas) receptor/ligand system and involves activation of wild-type p53 J. Clin. Invest. 99: 403–413
Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM . 1997 The CD95 (Apo-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells Cancer Res. 57: 3823–3829
Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K . 1999 Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction Blood 93: 3053–3063
Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT . 1999 Fas ligand independent, FADD-mediated activation of the Fas pathway by anticancer drugs J. Biol. Chem. 274: 7987–7992
Ferreira CG, Tolis C, Span SW, Peters GJ, van Lopik T, Kummer AJ, Pinedo HM, Giaccone G . 2000 Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway Clin. Cancer. Res. 6: 203–212
Jones DT, Ganeshaguru K, Virchis AE, Folarin NI, Lowdell MW, Mehta AB, Prentice HG, Hoffbrand AV, Wickremasinghe RG . 2001 Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or γ radiation Blood 98: 2800–2807
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ED, Green DR, Martin SJ . 1999 Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in caspase-9-dependent manner J. Cell. Biol. 144: 281–292
Bonney EA, Matzinger P . 1998 Much IDO about pregnancy Nat. Med. 4: 1128–1129
Grohmann U, Belladonna ML, Vacca C, Bianchi R, Fallarino F, Orabona C, Fioretti MC, Puccetti P . 2001 Positive regulatory role of IL-12 in macrophages and modulation by IFN-γ J. Immunol. 167: 221–227
Grohmann U, Belladonna ML, Bianchi R, Orabona C, Ayroldi E, Fioretti MC, Puccetti . 1998 IL-12 acts directly on DC to promote nuclear localization of NF-κB and primes DC for IL-12 production Immunity 9: 315–323
Fallarino F, Grohmann U, Bianchi R, Vacca C, Fioretti MC, Puccetti . 2000 Th1 and Th2 cell clones to a poorly immunogenic tumor antigen initiate CD8+ T cell-dependent tumor eradication in vivo J. Immunol. 165: 5495–5501
Grohmann U, Bianchi R, Ayroldi E, Belladonna ML, Surace D, Fioretti MC, Puccetti P . 1997 A tumor-associated and self antigen peptide presented by dendritic cells may induce T cell anergy in vivo, but IL-12 can prevent or revert the anergic state J. Immunol. 158: 3593–3602
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Can J, Peng TI, Jones DP, Wang X . 1997 Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked Science 275: 1129–1132
Acknowledgements
This work was supported by the Italian Association for Cancer Research (AIRC) and by a post-doctoral fellowship from FIRC (to F Fallarino).
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by J Cidlowski
Rights and permissions
About this article
Cite this article
Fallarino, F., Grohmann, U., Vacca, C. et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 9, 1069–1077 (2002). https://doi.org/10.1038/sj.cdd.4401073
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4401073
Keywords
This article is cited by
-
Activities of plasma indoleamine-2, 3-dioxygenase (IDO) enzyme in Nigerian patients with lung diseases: basis for tryptophan supplementation or IDO inhibitor use
The Egyptian Journal of Bronchology (2023)
-
Metabolomics profiling distinctively identified end-stage renal disease patients from chronic kidney disease patients
Scientific Reports (2023)
-
Raman spectroscopy and mass spectrometry identifies a unique group of epidermal lipids in active discoid lupus erythematosus
Scientific Reports (2023)
-
Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases
Molecular Biology Reports (2023)
-
Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment — Cell Type-Specific Findings (Part 2)
Current Allergy and Asthma Reports (2023)
