Daan Pieren

165 General discussion and future perspectives these cells remained to be explored. Our findings now indicate that aging drives immunosenescence of the CD8 + T-cell population already in the intermediate- differentiated state and therefore challenge the current view that primarily late- differentiated CD8 + T cells are immunosenescent. ACCUMULATION OF REGULATORY T CELLS WITH AGE Accumulation of regulatory T cells (Tregs) has been hypothesized to be one of the causes for reduced T-cell mediated protection observed during aging, as Tregs may dampen protective T-cell responses and their (relative) numbers increase with age. It has indeed been shown in mice that accumulated Tregs impair protective immune responses [17,18], and this is thought to be due to the sheer increase in Treg numbers, as the suppressive capacity remains comparable between Tregs of young and aged mice [17,19] and humans [20,21]. However, the underlying cause of Treg accumulation remained unclear. In chapter 2 we report accumulation of Tregs in the spleen of aged mice and we show that these cells were particularly enriched within their naive CD4 + T-cell subset. Moreover, we found similar accumulation of Tregs within the naive CD4 + T-cell pool of mice with a deficiency in the Ercc1 gene ( Ercc1 -/ Δ 7 mice) ( Chapter 3 ). Ercc1 - deficiency compromises several DNA damage repair mechanisms and leads to accumulation of DNA damage [22-24], which is an important hallmark of aging [25,26]. As a consequence, Ercc1 -/ Δ 7 mice age very rapidly and provide a model for cell intrinsic aging that minimizes the effects of aging on a chronological scale. From our findings in chapter 2 and 3 , we conclude that the accumulation of Tregs within the naive CD4 + T-cell subset is at least partly promoted by compromised DNA-repair. Placing our findings from chapter 2 and 3 within the current literature, we postulate a new potential mechanism that accounts for the accumulation of Tregs with age ( Figure 1 ). Senescent tissue cells are known to accumulate in several tissues and organs of wildtype aged and Ercc1 -deficient mice [27-29]. These senescent cells do not proliferate anymore, but secrete the senescence- associated secretory phenotype (SASP), which consists of pro-inflammatory factors, including IL-6 [30]. Increased levels of IL-6 have been observed in Ercc1 -deficient mice [27,31,32] and have also been reported in older adults [33]. Importantly, IL-6 increases in serum of wildtype aged mice and promotes accumulation of Tregs in these mice [34], indicating that elevated IL-6 at old age may be the driver of Treg accumulation. Based on these findings, we propose a potential mechanism in which the rise of senescent cells during aging is accompanied by increased levels of IL-6, that in turn drives the accumulation 6