title: Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells.
abstract: Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity. T-cell proliferation and differentiation to effector cells require increased glucose consumption, aerobic glycolysis and glutaminolysis. The effect of IDO on the above metabolic pathways was evaluated in alloreactive T-cells. Mixed lymphocyte reaction (MLR) in the presence or not of the IDO inhibitor, 1-methyl-dl-tryptophan (1-MT), was used. In MLRs, 1-MT decreased tryptophan consumption, increased cell proliferation, glucose influx and lactate production, whereas it decreased tricarboxylic acid cycle activity. In T-cells, from the two pathways that could sense tryptophan depletion, i.e. general control nonrepressed 2 (GCN2) kinase and mammalian target of rapamycin complex 1, 1-MT reduced only the activity of the GCN2 kinase. Additionally 1-MT treatment of MLRs altered the expression and/or the phosphorylation state of glucose transporter-1 and of key enzymes involved in glucose metabolism and glutaminolysis in alloreactive T-cells in a way that favors glucose influx, aerobic glycolysis and glutaminolysis. Thus in alloreactive T-cells, IDO through activation of the GCN2 kinase, decreases glucose influx and alters key enzymes involved in metabolism, decreasing aerobic glycolysis and glutaminolysis. Acting in such a way, IDO could be considered as a constraining factor for alloreactive T-cell proliferation and differentiation to effector T-cell subtypes.
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece. Electronic address: teleftheriadis@yahoo.com.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Eleftheriadis
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.forename: Efi
authors.initials: E
authors.lastname: Yiannaki
authors.forename: Dimitra
authors.initials: D
authors.lastname: Markala
authors.forename: Spyridon
authors.initials: S
authors.lastname: Arampatzis
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D000328:Adult; D002952:Citric Acid Cycle / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051272:Glucose Transporter Type 1; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D046912:Multiprotein Complexes; D014364:Tryptophan; C529271:EIF2AK4 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; C525396:1-methyltryptophan