title: Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation.
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.
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Jianqun
authors.initials: J
authors.lastname: Liao
authors.forename: Jeannine
authors.initials: J
authors.lastname: Villella
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Shashikant
authors.initials: S
authors.lastname: Lele
authors.forename: Protul
authors.initials: P
authors.lastname: Shrikant
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007737:Kynurenine / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; C525396:1-methyltryptophan