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Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation

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Abstract

IDO2 is a newly discovered enzyme with 43 % similarity to classical IDO (IDO1) protein and shares the same critical catalytic residues. IDO1 catalyzes the initial and rate-limiting step in the degradation of tryptophan and is a key enzyme in mediating tumor immune tolerance via arrest of T cell proliferation. The role of IDO2 in human T cell immunity remains controversial. Here, we demonstrate that similar to IDO1, IDO2 also degrades tryptophan into kynurenine and is inhibited more efficiently by Levo-1-methyl tryptophan (L-1MT), an IDO1 competitive inhibitor, than by dextro-methyl tryptophan (D-1MT). Although IDO2 enzyme activity is weaker than IDO1, it is less sensitive to 1-MT inhibition than IDO1. Moreover, our results indicate that human CD4+ and CD8+ T cell proliferation was inhibited by IDO2, but both L-1MT and D-1MT could not reverse IDO2-mediated arrest of cell proliferation, even at high concentrations. These data indicate that IDO2 is an inhibitory mechanism in human T cell proliferation and support efforts to develop more effective IDO1 and IDO2 inhibitors in order to overcome IDO-mediated immune tolerance.

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Acknowledgments

We thank Dr. Benoît J. Van den Eynde for providing us with 293IDO1 cells and Dr. Richard Metz for 293IDO2 cells. This work was supported by a grant from the Cancer Research Institute Ovarian Cancer Working Group Grant (K.O.) Anna-Marie Kellen Clinical Investigator Award of the CRI (to K.O.), the Ovarian Cancer Research Fund (K.O. and P.S.), and a Roswell Park Cancer Institute Alliance Foundation grant.

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The authors declare that they have no conflict of interest.

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Correspondence to Kunle Odunsi.

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Qian, F., Liao, J., Villella, J. et al. Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother 61, 2013–2020 (2012). https://doi.org/10.1007/s00262-012-1265-x

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  • DOI: https://doi.org/10.1007/s00262-012-1265-x

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