Daan Pieren

64 Chapter 3 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 -/ Δ 7 ) mice show accumulation of nuclear DNA damage resulting in accelerated aging. Similarly to wild-type aged mice, Ercc1 -/ Δ 7 mice accumulated naive Tregs with reduced CD25 and increased PD-1 expression in their spleen. 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 -/ Δ 7 mice with rapamycin did not reduce Treg levels, but highly increased the proportion of memory CD25 + and PD-1 + Tregs instead. Our study elucidates that compromised DNA repair promotes the accumulation of naive Tregs with an aging-related phenotype and causes reduced T-cell responsiveness, which may be independent of mTOR activation.