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

Daan K J Pieren, Noortje A M Smits, Sandra Imholz, Bhawani Nagarajah, Conny T van Oostrom, Renata M C Brandt, Wilbert P Vermeij, Martijn E T Dollé, Teun Guichelaar

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review


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.
Originele taal-2Engels
TijdschriftFrontiers in aging
StatusGepubliceerd - 11 mei 2021


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