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
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. © 2015 John Wiley & Sons Ltd.
Showing items related by title, author, creator and subject.
Indoleamine 2,3-dioxygenase, by degrading L-tryptophan, enhances carnitine palmitoyltransferase i activity and fatty acid oxidation, and exerts fatty acid-dependent effects in human alloreactive CD4+ T-cells Eleftheriadis T., Pissas G., Sounidaki M., Tsogka K., Antoniadis N., Antoniadi G., Liakopoulos V., Stefanidis I. (2016)Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen presenting cells and by degrading L-tryptophan along the kynurenine pathway suppresses CD4+ T-cell proliferation, induces apoptosis and promotes differentiation ...
Crystalline silica activates the T-cell and the B-cell antigen receptor complexes and induces T-cell and B-cell proliferation Eleftheriadis T., Pissas G., Zarogiannis S., Liakopoulos V., Stefanidis I. (2019)Silicosis is an occupational fibrotic lung disease, which is associated with an increased incidence of autoimmune diseases. The effect of crystalline silica on the immune system is thought to be mediated by the antigen ...
In human alloreactive CD4+ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets Eleftheriadis T., Sounidaki M., Pissas G., Antoniadi G., Liakopoulos V., Stefanidis I. (2016)Although kidney transplantation is the best therapy for end-stage renal disease, rejection remains a concern, and currently available immunosuppressive agents contribute to morbidity and mortality. Thus, novel immunosuppressive ...