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Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules

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T-cell activation upon antigen stimulation is essential for the continuation of the adaptive immune response. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T-cell activation. Dihydroorotate dehydrogenase (DHODH) is a component of the de novo synthesis of pyrimidines, the activity of which depends on functional oxidative phosphorylation. Under circumstances of an inhibited oxidative phosphorylation, DHODH becomes rate-limiting. Inhibition of DHODH is known to block clonal expansion and expression of effector molecules of activated T cells. However, this effect has been suggested to be caused by downstream impairment of oxidative phosphorylation rather than a lower rate of pyrimidine synthesis. In this study, we successfully inhibit the DHODH of T cells with no residual effect on oxidative phosphorylation and demonstrate a dose-dependent inhibition of proliferation of activated CD3+ T cells. This block is fully rescued when uridine is supplemented. Inhibition of DHODH does not alter expression of effector molecules but results in decreased intracellular levels of deoxypyrimidines without decreasing cell viability. Our results clearly demonstrate the DHODH and mitochondrial linked pyrimidine synthesis as an independent and important cytostatic regulator of activated T cells.

Original languageEnglish
Article number718863
JournalFrontiers in Immunology
Volume12
Pages (from-to)718863
ISSN1664-3224
DOIs
Publication statusPublished - 24 Nov 2021

Bibliographical note

Publisher Copyright:
Copyright © 2021 Peeters, Aehnlich, Pizzella, Mølgaard, Seremet, Met, Rasmussen, thor Straten and Desler.

    Research areas

  • immunosenescence and exhaustion, mitochondrial respiration and oxidative respiration, pyrimidine de novo synthesis, T-cell activation, T-cell metabolism, Pyrimidines/biosynthesis, Humans, Cell Proliferation/physiology, Dihydroorotate Dehydrogenase/antagonists & inhibitors, Lymphocyte Activation/immunology, Mitochondria/drug effects

ID: 72731153