Daan Pieren

65 Compromised DNA repair promotes the accumulation of regulatory T cells INTRODUCTION The phenotype and functionality of T cells change during the course of aging, which contributes to aging-related pathology, increased susceptibility to infectious diseases, and reduced vaccine efficacy in the elderly [1]. The decline in T-cell function with age can in part be explained by changes to their phenotype and proliferative capacity, often referred to as T-cell exhaustion and/ or T-cell senescence [2]. Additionally, we and others have shown that FoxP3 + regulatory T cells accumulate with age [3-8] and it is thought that these cells impair protective immune responses by their suppressive capacity [4,5,9]. Insight into biological processes that contribute to decreased T-cell function and the accumulation of regulatory T cells (Tregs) with age is required to better understand the process of T-cell aging. Characteristics of T-cell aging are mostly investigated on a chronological scale, i.e. changes that occur among T cells in relation to progressing time. Indeed, the exposure of antigens over a lifetime causes major alterations to the T-cell compartment [10]. Aside from this standard pathway, aging is also driven by cell intrinsic processes such as the accumulation of nuclear DNA damage; a hallmark of aging and recently defined as the factor driving all other hallmarks of aging [11,12]. Accumulation of DNA damage with age is a result of suboptimal DNA repair and is thought to be one of the drivers of cellular senescence [13- 15]. This may also apply to aging of T cells, as T cells with a highly differentiated phenotype accumulate with age [16] and express higher levels of DNA damage [17]. However, to what extent characteristics of T-cell aging are explained by suboptimal DNA repair remains unclear. In this study, we defined the impact of compromised DNA repair on hallmarks of T-cell aging. The endonuclease complex ERCC1-XPF mediates the repair of a broad variety of DNA lesions: I) bulky helix-distorting lesions are removed by global- genome nucleotide excision repair; II) lesions blocking transcription are removed by transcription-coupled repair; III) DNA crosslinks are removed via interstrand crosslink repair; and IV) a subset of persisting double-strand DNA breaks are removed by the single-strand annealing pathway [18,19]. Mice with a deficiency in the DNA excision-repair gene Ercc1 ( Ercc1 -/ Δ 7 ) have one knock-out and one truncated allele of Ercc1 and therefore show impaired DNA repair within the four aforementioned pathways, which results in the accumulation of nuclear DNA damage [20-22]. As a consequence, Ercc1 -/ Δ 7 mice show numerous age-related pathologies and signs of accelerated aging with a reduced average lifespan of only 20 weeks [12,23,24]. Ercc1 -/ Δ 7 mice therefore provide an aging model 3