Indoleamine 2,3-dioxygenase increases p53 levels in alloreactive human T cells, and both indoleamine 2,3-dioxygenase and p53 suppress glucose uptake, glycolysis and proliferation

Abstract

Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity by inhibiting T-cell proliferation and altering glucose metabolism. The tumor suppressor p53 also alters these cellular processes with similar results. The effect of IDO on p53 and on glucose metabolism was evaluated in alloreactive T cells. Mixed-lymphocyte reactions (MLRs) were performed in the presence or not of the IDO inhibitor, 1-dl-methyl-tryptophan (1-MT) and/or the p53 inhibitor, pifithrin-α (PFT). Cell proliferation, glucose consumption and lactate production were assessed. 1-MT increased cell proliferation, glucose influx and lactate production, whereas PFT enhanced cell proliferation and glucose influx, leaving lactate production unaffected. In MLR-derived T cells, protein analysis revealed that IDO activated general control non-derepressible 2 kinase and induced p53, p-p53 (p53 phosphorylated at serine 15) and p21. In addition, both IDO and p53 decreased glucose transporter 1 and TP53-induced glycolysis and apoptosis regulator and increased synthesis of cytochrome c oxidase 2. IDO also reduced lactate dehydrogenase-A and glutaminase 2 levels, whereas p53 left them unaffected. Neither 1-MT nor PFT affected glucose-6-phosphate dehydrogenase. In conclusion, in alloreactive T cells, IDO increases p53 levels, and both IDO and p53 inhibit cell proliferation, glucose consumption and glycolysis. Lactate production and glutaminolysis are also suppressed by IDO, but not by p53.

Angiogenin is upregulated during the alloreactive immune response and has no effect on the T-cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T-cell apoptosis

“…In the absence of nuclear angiogenin, such as when neamine is used, p53 accumulates and increases the expression of its pro-apoptotic transcriptional targets, including Bax, leading to apoptosis (8). A recent study found that in T-cells isolated from MLRs conducted under the same conditions as the present study, p53 and phosphorylated p53 were robustly expressed (22). In conclusion, the results of the present study show that angiogenin is upregulated during the alloreactive adaptive immune response.…”

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

“…In addition to its role in aminoacylation, WARS, like many other tRNA synthethases 41-43 , has been implicated in cellular signaling. A truncated version of WARS is secreted in response to IFNγ and elicits angiostatic effects 23 through inhibition of endothelial cell-cell junctions 24 .…”

Role of indoleamine 2,3-dioxygenase in health and disease

“…The above findings therefore indicate that IDO1-catalysed LTrp depletion, the synthesis of Kyn pathway metabolites and the activation of AhR and other signalling pathways control the activation status, phenotype and viability of T-cells, B-cells and NK cells in various ways including: (i) induction of cell cycle arrest in T-cells and induction of cell death in T-cells, B-cells and NK cells [51,[229][230][231], (ii) impairment of NK cell-mediated killing by preventing the up-regulation of the activating receptors NKp46 and NKG2D [115], (iii) Th2 polarisation of invariant NKT cells [237], (iv) apoptosis of Th1 cells but not Th2 cells [238], (v) interfering with glucose metabolism in effector T-cells to inhibit proliferation [239,240], (vi) defective TCR activation via the interruption of Ca 2+ signalling [241], (vii) down-regulation of the ζ -chain in the TCR complex on CD8 + T-cells [232], (viii) acquisition and maintenance of an immunosuppressive Foxp3 + Treg (rather than a pro-inflammatory Th17) phenotype by naïve CD4 + T-cells [232,[242][243][244] involving the IDO1-and Kyn/AhRdependent blockade of the down-regulation of the Eos transcription factor (necessary for reprogramming of Tregs into Th17 inflammatory helper-like cells) [245], and (ix) direct activation of the suppressor activity of Foxp3 + Tregs involving the PD-1 (programmed cell death 1)/PD-L (programmed cell death ligand) pathway [226].…”