Indoleamine 2,3-dioxygenase downregulates T-cell receptor complex ζ-chain and c-Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T-cells

Abstract

Indoleamine 2,3-dioxygenase (IDO), through L-tryptophan depletion, activates general control non-derepressible (GCN) 2 kinase and suppresses T-cell proliferation, in addition to suppressing aerobic glycolysis and glutaminolysis, which are required for these rapidly proliferating cells. A number of, however not all of these alterations, are partially mediated through IDO-induced p53 upregulation. In two-way mixed lymphocyte reactions (MLRs), IDO reduced cellular proliferation. In MLR-derived T-cells, IDO induced the expression levels of p53 and p21, however concurrently reduced the levels of ζ-chain, c-Myc, lactate dehydrogenase A (LDH-A) and glutaminase (GLS)2. However, p53 had no effect on the expression of the above proteins. These results were recapitulated in T-cells activated with anti-CD2, anti-CD3 and anti-CD28 by direct activation of the GCN2 kinase with tryptophanol. In conclusion, IDO, through GCN2 kinase activation, downregulates the levels of TCR-complex ζ-chain and c-Myc, resulting in the suppression of T-cell proliferation and a reduction in the levels of LDH-A and GLS2, which are key enzymes involved in aerobic glycolysis and glutaminolysis, respectively.