title: Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells.
abstract: Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen-presenting cells and exerts immunosuppressive effects on CD4(+) T cells. One mechanism is through the inhibition of aerobic glycolysis. Another prerequisite for T-cell proliferation and differentiation into effector cells is increased fatty acid (FA) synthesis. The effect of IDO on enzymes involved in FA synthesis was evaluated in primary human cells both in mixed lymphocyte reactions in the presence or not of the IDO inhibitor 1-dl-methyl-tryptophan, and in stimulated CD4(+) T cells in the presence or not of the general control non-derepressible 2 (GCN2) kinase activator tryptophanol (TRP). IDO or TRP inhibited cell proliferation. By assessing the level of GCN2 kinase or mammalian target of rapamycin complex 1 substrates along with a kynurenine free system we showed that IDO exerts its effect mainly through activation of GCN2 kinase. IDO or TRP down-regulated ATP-citrate lyase and acetyl coenzyme A carboxylase 1, key enzymes involved in FA synthesis. Also, IDO or TRP altered the expression of enzymes that control the availability of carbon atoms for FA synthesis, such as lactate dehydrogenase-A, pyruvate dehydrogenase, glutaminase 1 and glutaminase 2, in a way that inhibits FA synthesis. In conclusion, IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages.
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Eleftheriadis
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D005227:Fatty Acids / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014364:Tryptophan / Q000172:deficiency*
chemical_list: D005227:Fatty Acids; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D014364:Tryptophan; C529271:EIF2AK4 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: ATP-citrate lyase; T cells; acetyl coenzyme A carboxylase 1; fatty acid; general control non-derepressible 2 kinase; indoleamine 2,3-dioxygenase