Daan Pieren

13 General introduction and scope of this thesis Additionally, both the CD4 + and the CD8 + T-cell populations comprise regulatory T cells (Tregs). Tregs are capable of suppressing the activation and proliferation of other T cells, as well as other cells of the immune system [45]. Tregs are highly important cells as they maintain homeostasis within the immune system: dampening anti-viral cytotoxic T-cell responses adequately enough to minimize immunopathology, while still allowing killing of infected cells by cytotoxic T cells. However, it has been reported that Tregs accumulate during aging, leading to the hypothesis that declined immune responses observed with age can be partly attributed to the accumulation of suppressive Tregs ( Figure 1 ). CD4 + Regulatory T cells The importance of CD4 + Tregs was shown by one of the pioneering T REG studies reporting that CD25 + CD4 + T cells can prevent devastating autoimmune disease [46]. Later studies identified Forkhead Box P3 (FoxP3) as the transcription factor that characterizes suppressive Tregs in mice and humans [47-49]. Additionally, Tregswere also found to be highly important to prevent viral lung disease [50]. Importantly, it has been shown that aged mice accumulated Tregs [51-55] and this accumulation led to impaired protective immune responses in these mice [51,52,55]. However, the accumulation of Tregswith aging appears to depend on the site investigated: aged mice accumulate Tregs in their lymphoid organs (although not in the thymus). Observations on accumulation of Tregs in peripheral blood of aged mice are not all consistent, although most studies do not find increased T REG levels [51]. In line with this, studies remain inconclusive whether Tregs accumulate in the peripheral blood of older humans, showing both increased [51,56,57] and stable T REG levels [58,59]. A study that assessed the proportion of human Tregs outside of the blood indicate accumulation of Tregs with aging in human skin [60]. Thus, mostly mouse-derived evidence seems to point towards accumulation of Tregs outside of the peripheral blood, thereby maintaining the hypothesis that this accumulation may dampen protective responses in the elderly ( Figure 1 ). However, how and why Tregs accumulate with age remains to be elucidated. CD8 + Regulatory T cells Whereas the existence of CD4 + Tregs has been widely described and accepted, the existence of CD8 + Tregs is more unclear and controversial as CD8 + T cells are mostly regarded as efficient killer cells targeting infected or abnormal cells. However, evidence for CD8 + Tregs is re-emerging after the initial studies reporting on CD8 + Tregs in the 1970’s [61,62]. The phenotype of CD8 + Tregs that distinguishes these cells from conventional CD8 + T cells is currently still under 1