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

Frontiers in Immunology

Adriano Pizzella¹  Claus Desler¹  Lene Juel Rasmussen¹  Per thor Straten²  Özcan Met²  Tina Seremet³  Marlies J. W. Peeters³  Kasper Mølgaard³  Pia Aehnlich³ 

[1] Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark;Department of Immunology and Microbiology, Inflammation and Cancer Group, University of Copenhagen, Copenhagen, Denmark;National Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Copenhagen, Denmark;

关键词: T-cell metabolism;    T-cell activation;    pyrimidine de novo synthesis;    mitochondrial respiration and oxidative respiration;    immunosenescence and exhaustion;   

DOI  :  10.3389/fimmu.2021.718863

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown