Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation |
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Authors: | Feng Qian Jianqun Liao Jeannine Villella Robert Edwards Pawel Kalinski Shashikant Lele Protul Shrikant Kunle Odunsi |
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Institution: | 1. Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA 3. Roswell Park Cancer Institute, Center for Immunotherapy, Elm & Carlton Streets, Buffalo, NY, 14263, USA 4. Division of Gynecologic Oncology, Winthrop-University Hospital, New York, NY, USA 5. Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 6. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 2. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA
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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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