Daan Pieren

166 Chapter 6 of Tregs. Possibly, the accumulation of Tregs is a mechanism to counter the pro-inflammatory microenvironment created by senescent cells secreting the SASP. Local and tissue-specific secretion of pro-inflammatory proteins may therefore also explain why accumulation of Tregs has mostly been reported to occur outside of the peripheral blood [17]. Whether IL-6 directly interacts with Tregs and promotes Treg expansion or whether this occurs indirectly remains to be established. Thus, the findings presented in chapter 2 and 3 of this thesis provide the link between aging, cellular senescence, inflammaging, and the accumulation of Tregs as shown in Figure 1 . Lastly, our hypothesis that Tregs accumulate as a consequence of senescence-induced inflammation may also provide a potential link to the accumulation of regulatory KIR + RA + T cells at older age as we report on in chapter 5 . We found that KIR + RA +  T cells highly express the transcription factor Helios. Interestingly, a recent study shows that the proportion of Helios + CD8 + T cells positively correlates with plasma levels of pro-inflammatory factors, such as IP-10, TNF, and IL-6 in HIV-infected individuals [35]. Part of these Helios + CD8 + T cells described in this report likely comprise KIR + RA + T cells. The association between Helios + CD8 + T cells and pro-inflammatory factors described in this report may indicate that a similar event occurs during the course of aging: increased pro-inflammatory plasma levels increase the abundance of T cells with a regulatory profile to counterbalance the pro-inflammatory environment. It would therefore be highly interesting to assess whether pro-inflammatory cytokine levels are also increased in individuals with higher KIR + RA + T-cell proportions. Moreover, promoting or blocking pro-inflammatory factors in future in vivo mouse studies should provide evidence whether the proportion of the murine equivalent of KIR + RA + T cells alters within a pro-inflammatory microenvironment. Potentially, KIR + RA + T cells could be used as a biological marker for an increased inflammatory state.