The Journal of Experimental Medicine
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Published online 12 August 2002 doi:10.1084/jem.20020121
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© Rockefeller University Press, 0022-1007/2002/8/459/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 459-468

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

Guido Frumento1, Rita Rotondo1, Michela Tonetti2, Gianluca Damonte2, Umberto Benatti2 and Giovanni Battista Ferrara1,3

1 Immunogenetics Laboratory, National Cancer Research Institute
2 Biochemistry Section, Experimental Medicine Department
3 Oncology, Biology and Genetics Department, University of Genoa, and Advanced Biotechnology Center, 16132 Genoa, Italy

Address correspondence to Dr. Guido Frumento, Immunogenetics Laboratory, c/o CBA-Torre A2, Largo Rosanna Benzi 10, 16132 Genoa, Italy. Phone: 39 010 5737228; Fax: 39 010 5737237: E-mail: guido.frumento{at}istge.it

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.

Key Words: T cell proliferation • macrophages • indoleamine 2,3-dioxygenase • tryptophan • kynurenine


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