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

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 pyrimidi...

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Autores principales:	Marlies J. W. Peeters, Pia Aehnlich, Adriano Pizzella, Kasper Mølgaard, Tina Seremet, Özcan Met, Lene Juel Rasmussen, Per thor Straten, Claus Desler
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	T-cell metabolism T-cell activation pyrimidine de novo synthesis mitochondrial respiration and oxidative respiration immunosenescence and exhaustion Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/d07890576b8949e18e9b8caa7c3ef5cf
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spelling	oai:doaj.org-article:d07890576b8949e18e9b8caa7c3ef5cf2021-11-30T18:57:30ZMitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules1664-322410.3389/fimmu.2021.718863https://doaj.org/article/d07890576b8949e18e9b8caa7c3ef5cf2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.718863/fullhttps://doaj.org/toc/1664-3224T-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.Marlies J. W. PeetersPia AehnlichAdriano PizzellaKasper MølgaardTina SeremetÖzcan MetÖzcan MetLene Juel RasmussenPer thor StratenPer thor StratenClaus DeslerFrontiers Media S.A.articleT-cell metabolismT-cell activationpyrimidine de novo synthesismitochondrial respiration and oxidative respirationimmunosenescence and exhaustionImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	T-cell metabolism T-cell activation pyrimidine de novo synthesis mitochondrial respiration and oxidative respiration immunosenescence and exhaustion Immunologic diseases. Allergy RC581-607
spellingShingle	T-cell metabolism T-cell activation pyrimidine de novo synthesis mitochondrial respiration and oxidative respiration immunosenescence and exhaustion Immunologic diseases. Allergy RC581-607 Marlies J. W. Peeters Pia Aehnlich Adriano Pizzella Kasper Mølgaard Tina Seremet Özcan Met Özcan Met Lene Juel Rasmussen Per thor Straten Per thor Straten Claus Desler Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
description	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.
format	article
author	Marlies J. W. Peeters Pia Aehnlich Adriano Pizzella Kasper Mølgaard Tina Seremet Özcan Met Özcan Met Lene Juel Rasmussen Per thor Straten Per thor Straten Claus Desler
author_facet	Marlies J. W. Peeters Pia Aehnlich Adriano Pizzella Kasper Mølgaard Tina Seremet Özcan Met Özcan Met Lene Juel Rasmussen Per thor Straten Per thor Straten Claus Desler
author_sort	Marlies J. W. Peeters
title	Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
title_short	Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
title_full	Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
title_fullStr	Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
title_full_unstemmed	Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
title_sort	mitochondrial-linked de novo pyrimidine biosynthesis dictates human t-cell proliferation but not expression of effector molecules
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d07890576b8949e18e9b8caa7c3ef5cf
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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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