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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules. / Peeters, Marlies J.W.; Aehnlich, Pia; Pizzella, Adriano; Mølgaard, Kasper; Seremet, Tina; Met, Özcan; Rasmussen, Lene Juel; thor Straten, Per; Desler, Claus.

In: Frontiers in Immunology, Vol. 12, 718863, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Peeters, MJW, Aehnlich, P, Pizzella, A, Mølgaard, K, Seremet, T, Met, Ö, Rasmussen, LJ, thor Straten, P & Desler, C 2021, 'Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules', Frontiers in Immunology, vol. 12, 718863. https://doi.org/10.3389/fimmu.2021.718863

APA

Peeters, M. J. W., Aehnlich, P., Pizzella, A., Mølgaard, K., Seremet, T., Met, Ö., Rasmussen, L. J., thor Straten, P., & Desler, C. (2021). Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules. Frontiers in Immunology, 12, [718863]. https://doi.org/10.3389/fimmu.2021.718863

Vancouver

Peeters MJW, Aehnlich P, Pizzella A, Mølgaard K, Seremet T, Met Ö et al. Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules. Frontiers in Immunology. 2021;12. 718863. https://doi.org/10.3389/fimmu.2021.718863

Author

Peeters, Marlies J.W. ; Aehnlich, Pia ; Pizzella, Adriano ; Mølgaard, Kasper ; Seremet, Tina ; Met, Özcan ; Rasmussen, Lene Juel ; thor Straten, Per ; Desler, Claus. / Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules. In: Frontiers in Immunology. 2021 ; Vol. 12.

Bibtex

@article{d7bebd3e318b4edfbfdd15930e571875,

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

abstract = "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.",

keywords = "immunosenescence and exhaustion, mitochondrial respiration and oxidative respiration, pyrimidine de novo synthesis, T-cell activation, T-cell metabolism",

author = "Peeters, {Marlies J.W.} and Pia Aehnlich and Adriano Pizzella and Kasper M{\o}lgaard and Tina Seremet and {\"O}zcan Met and Rasmussen, {Lene Juel} and {thor Straten}, Per and Claus Desler",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 Peeters, Aehnlich, Pizzella, M{\o}lgaard, Seremet, Met, Rasmussen, thor Straten and Desler.",

year = "2021",

doi = "10.3389/fimmu.2021.718863",

language = "English",

volume = "12",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

RIS

TY - JOUR

T1 - Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules

AU - Peeters, Marlies J.W.

AU - Aehnlich, Pia

AU - Pizzella, Adriano

AU - Mølgaard, Kasper

AU - Seremet, Tina

AU - Met, Özcan

AU - Rasmussen, Lene Juel

AU - thor Straten, Per

AU - Desler, Claus

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - immunosenescence and exhaustion

KW - mitochondrial respiration and oxidative respiration

KW - pyrimidine de novo synthesis

KW - T-cell activation

KW - T-cell metabolism

U2 - 10.3389/fimmu.2021.718863

DO - 10.3389/fimmu.2021.718863

M3 - Journal article

C2 - 34899685

AN - SCOPUS:85120923026

VL - 12

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 718863

ER -

ID: 287629507