Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness.

Autor:	Pieren DKJ; Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., Smits NAM; Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., Imholz S; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., Nagarajah B; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., van Oostrom CT; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., Brandt RMC; Department of Molecular Genetics, Erasmus MC, Rotterdam, Netherlands., Vermeij WP; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Dollé MET; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands., Guichelaar T; Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in aging [Front Aging] 2021; Vol. 2. Date of Electronic Publication: 2021 May 11.
DOI:	10.3389/fragi.2021.667193
Abstrakt:	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. Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Databáze:	MEDLINE
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