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 TITLE=Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness JOURNAL=Frontiers in Aging VOLUME=2 YEAR=2021 URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2021.667193 DOI=10.3389/fragi.2021.667193 ISSN=2673-6217 ABSTRACT=

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.