Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase

By G. Frumento, R. Rotondo, M. Tonetti, G. Damonte, U. Benatti, G. Ferrara. Journal of Experimental Medicine, 2002

1,155 citations recorded by the source corpus.

Macrophages exposed to macrophage colony-stimulating factor acquire the capacity to suppress T cell proliferation; this effect is associated with de novo expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). We have purified IDO and tested its activity in in vitro models of T cell activation. IDO was able to inhibit proliferation of CD4+ T lymphocytes, CD8+ T lymphocytes, and natural killer (NK) cells; proliferation of B lymphocytes was not affected. The inhibitory role of tryptophan and of its catabolites was then tested. In the presence of tryptophan, only l-kynurenine and picolinic acid inhibit cell proliferation. In a tryptophan-free medium cell proliferation was not affected. In the absence of tryptophan inhibition induced by l-kynurenine and picolinic acid was observed at concentrations below the lowest concentration that was effective in the presence of tryptophan, and quinolinic acid acquired some inhibitory capacity. Inhibition of cell proliferation induced by the tryptophan catabolites resulting from IDO activity was selective, applying only to cells undergoing activation. Resting cells were not affected and could subsequently activate normally. We suggest that IDO exerts its effect on cell proliferation by (i) starting the cascade of biochemical reactions that produce the three catabolites and by (ii) enhancing their inhibitory potential by depriving the extracellular microenvironment of tryptophan.

Subfields: Behavioral Neuroscience, Biological Psychiatry, Neurology

View Paper: https://www.semanticscholar.org/paper/d60d08c71b76340261945694739a65d662d27c86

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Citations in the corpus

Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. (2004, background): “antimicrobial (60, 61) and antiviral (62, 63) effects, and inhibition of T cell proliferation in some models (18, 25, 64); and (b) effects mediated by toxic downstream metabolites of tryptophan, which include CD4+ T cell apoptosis (65) and inhibition of T cell proliferation in other models (66, 67).”
Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health (2017, background): “This receptor is expressed in human CD14+monocytes, T cells, neutrophils, DCs, eosinophils, basophils and invariant NKT (iNKT) cells (13, 74).”
The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 (2006, background): “Although the mechanisms of kynurenine action are largely unknown (17, 25, 53, 54), this observation clearly distinguishes the activity of IDO as a truly immunoregulatory enzyme from the effects on T cells of a mere starvation for amino acids, and paves the way to the possible use of synthetic kynure”
Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript accumulation of MDSCs and inhibiting T cell function (Raber, Ochoa, & Rodríguez, 2012).”
Dendritic cells: translating innate to adaptive immunity. (2006, background): “tential suppressive pathway inDCs entails the induction of active indoleamine dioxygenase, which can be toxic to lymphocytes [190–192].”
Ido expression by dendritic cells: tolerance and tryptophan catabolism (2004, background): “Human T cells were also found to be sensitive to the anti-proliferative and cytotoxic effects of exogenously added kynurenine, picolinic acid and 3-hydroxy-anthranilic aci”