Daan Pieren

80 Chapter 3 DISCUSSION Aging has a significant effect on T-cell phenotype and responsiveness, which contributes to pathology, increased susceptibility to infectious diseases, and reduced vaccine efficacy in the elderly [1]. Aside from well described T-cell aging phenomena that occur over time, the contribution of intracellular processes that drive T-cell aging such as compromised DNA repair remain incompletely defined. Here we provide novel insights into T-cell aging as we show which parts of T-cell aging can be attributed to compromised DNA repair. Moreover, we show that the majority of the changes to T cells induced by compromised DNA-repair could not be reversed by inhibition of mTOR activation. Accumulation of Tregs during aging has been described in mice and humans [3-8] and is thought to limit protective immune responses. However, the underlying cause of Treg accumulation with age remains unclear. Here we discovered that compromised DNA repair contributes to the accumulation of Tregs observed during aging, as we show that Tregs accumulate in Ercc1 -/ Δ 7 and WT aged mice. Similar to WT aged mice, Treg accumulation in Ercc1 -/ Δ 7 mice was explained by an increase in the proportion of Tregs within the naive CD4 + T-cell subset. Consistent with previous findings in WT mice [3,8], these Tregs showed an age-related phenotype characterized by increased expression of PD-1 and decreased expression of CD25. Thus, our data indicate that compromised DNA repair may be a contributing factor in promoting Treg accumulation previously observed to occur during the process of aging. An important question that now remains is how compromised DNA repair results in the accumulation of Tregs. We predict that compromised DNA-damage repair in cells that make up the micro-environment of T cells significantly contributes to the phenotypical and functional changes found within the T cell pool with age. Senescent cells develop during the process of aging in multiple organs partly due to intracellular accumulation of DNA damage [38,39]. These cells are known to secrete a collection of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). Accumulation of senescent cells therefore results in an inflammatory micro-environment [38]. Interestingly, it has been reported that the cytokine IL-6 is part of the pro-inflammatory SASP and promotes the accumulation of Tregs in WT aged mice [40]. Moreover, it is known that Ercc1 -/ Δ 7 mice also accumulate senescent cells and show increased levels of the SASP, including higher levels of IL-6 in several organs and serum [21,41-43]. Based on these and our findings, we speculate that accumulation of Tregs with age is mediated by pro-inflammatory factors like IL-6 secreted by senescent cells that result from