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Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness
Decline of immune function during aging has in part been ascribed to the accumulation of regulatory T cells (Tregs) and decreased T-cell responses with age. Aside from changes to T cells that occur over a lifetime, the impact of intracellular aging processes such as compromised DNA repair on T cells...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037984/ https://www.ncbi.nlm.nih.gov/pubmed/35474946 http://dx.doi.org/10.3389/fragi.2021.667193 |
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author | Pieren, Daan K. J. Smits, Noortje A. M. Imholz, Sandra Nagarajah, Bhawani van Oostrom, Conny T. Brandt, Renata M. C. Vermeij, Wilbert P. Dollé, Martijn E. T. Guichelaar, Teun |
author_facet | Pieren, Daan K. J. Smits, Noortje A. M. Imholz, Sandra Nagarajah, Bhawani van Oostrom, Conny T. Brandt, Renata M. C. Vermeij, Wilbert P. Dollé, Martijn E. T. Guichelaar, Teun |
author_sort | Pieren, Daan K. J. |
collection | PubMed |
description | Decline of immune function during aging has in part been ascribed to the accumulation of regulatory T cells (Tregs) and decreased T-cell responses with age. Aside from changes to T cells that occur over a lifetime, the impact of intracellular aging processes such as compromised DNA repair on T cells remains incompletely defined. Here we aimed to define the impact of compromised DNA repair on T-cell phenotype and responsiveness by studying T cells from mice with a deficiency in their DNA excision-repair gene Ercc1. These Ercc1 mutant (Ercc1 ( −/Δ7 )) mice show accumulation of nuclear DNA damage resulting in accelerated aging. Similarly to wild-type aged mice, Ercc1 ( −/Δ7 ) mice accumulated Tregs with reduced CD25 and increased PD-1 expression among their naive T cells. Ercc1-deficiency limited the capacity of Tregs, helper T cells, and cytotoxic T cells to proliferate and upregulate CD25 in response to T-cell receptor- and IL-2-mediated stimulation. The recent demonstration that the mammalian target of rapamycin (mTOR) may impair DNA repair lead us to hypothesize that changes induced in the T-cell population by compromised DNA repair may be slowed down or reversed by blocking mTOR with rapamycin. In vivo dietary treatment of Ercc1 ( −/Δ7 ) mice with rapamycin did not reduce Treg levels, but highly increased the proportion of CD25(+) and PD-1(+) memory Tregs instead. Our study elucidates that compromised DNA repair promotes the accumulation of Tregs with an aging-related phenotype and causes reduced T-cell responsiveness, which may be independent of mTOR activation. |
format | Online Article Text |
id | pubmed-9037984 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90379842022-04-25 Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness Pieren, Daan K. J. Smits, Noortje A. M. Imholz, Sandra Nagarajah, Bhawani van Oostrom, Conny T. Brandt, Renata M. C. Vermeij, Wilbert P. Dollé, Martijn E. T. Guichelaar, Teun Front Aging Aging Decline of immune function during aging has in part been ascribed to the accumulation of regulatory T cells (Tregs) and decreased T-cell responses with age. Aside from changes to T cells that occur over a lifetime, the impact of intracellular aging processes such as compromised DNA repair on T cells remains incompletely defined. Here we aimed to define the impact of compromised DNA repair on T-cell phenotype and responsiveness by studying T cells from mice with a deficiency in their DNA excision-repair gene Ercc1. These Ercc1 mutant (Ercc1 ( −/Δ7 )) mice show accumulation of nuclear DNA damage resulting in accelerated aging. Similarly to wild-type aged mice, Ercc1 ( −/Δ7 ) mice accumulated Tregs with reduced CD25 and increased PD-1 expression among their naive T cells. Ercc1-deficiency limited the capacity of Tregs, helper T cells, and cytotoxic T cells to proliferate and upregulate CD25 in response to T-cell receptor- and IL-2-mediated stimulation. The recent demonstration that the mammalian target of rapamycin (mTOR) may impair DNA repair lead us to hypothesize that changes induced in the T-cell population by compromised DNA repair may be slowed down or reversed by blocking mTOR with rapamycin. In vivo dietary treatment of Ercc1 ( −/Δ7 ) mice with rapamycin did not reduce Treg levels, but highly increased the proportion of CD25(+) and PD-1(+) memory Tregs instead. Our study elucidates that compromised DNA repair promotes the accumulation of Tregs with an aging-related phenotype and causes reduced T-cell responsiveness, which may be independent of mTOR activation. Frontiers Media S.A. 2021-05-11 /pmc/articles/PMC9037984/ /pubmed/35474946 http://dx.doi.org/10.3389/fragi.2021.667193 Text en Copyright © 2021 Pieren, Smits, Imholz, Nagarajah, van Oostrom, Brandt, Vermeij, Dollé and Guichelaar. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Aging Pieren, Daan K. J. Smits, Noortje A. M. Imholz, Sandra Nagarajah, Bhawani van Oostrom, Conny T. Brandt, Renata M. C. Vermeij, Wilbert P. Dollé, Martijn E. T. Guichelaar, Teun Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title | Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title_full | Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title_fullStr | Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title_full_unstemmed | Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title_short | Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness |
title_sort | compromised dna repair promotes the accumulation of regulatory t cells with an aging-related phenotype and responsiveness |
topic | Aging |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037984/ https://www.ncbi.nlm.nih.gov/pubmed/35474946 http://dx.doi.org/10.3389/fragi.2021.667193 |
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