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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 CD 4 + T cells
Author(s) -
Eleftheriadis Theodoros,
Pissas Georgios,
Antoniadi Georgia,
Liakopoulos Vassilios,
Stefanidis Ioannis
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12502
Subject(s) - enzyme , key (lock) , chemistry , kinase , tryptophan , biochemistry , primary (astronomy) , biology , amino acid , physics , ecology , astronomy
Summary Indoleamine 2,3‐dioxygenase ( IDO ) is expressed in antigen‐presenting cells and exerts immunosuppressive effects on CD 4 + 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 CD 4 + T cells in the presence or not of the general control non‐derepressible 2 ( GCN 2) kinase activator tryptophanol ( TRP ). IDO or TRP inhibited cell proliferation. By assessing the level of GCN 2 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 GCN 2 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 GCN 2 kinase activation inhibits CD 4 + T‐cell proliferation and down‐regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD 4 + T‐cell proliferation and differentiation into effector cell lineages.