Daan Pieren

177 General discussion and future perspectives antigen-specific response. Second, we found that activated KIR + RA + T cells are not specific for the highly conserved and immunodominant influenza A epitope GILGFVFTL, which may indicate a bystander role for these cells. However, whereas the response of CD8 + T cells is immunodominant when GILGFVFTL is restricted by HLA-A*02, we cannot exclude that KIR + RA + T cells recognize the GILGFVFTL epitope restricted by HLA-C*08 [83] via interaction with their KIR [66]. Third, to further provide evidence for a bystander role of KIR + RA + T cells, we also assessed their presence and activation status in SARS-CoV-2 infected adults. Since humans were considered naive to this new virus at the time of our study, we would not expect a large pool of specific memory T cells responding during the event of COVID-19 in the patients included in our study. Although it has been shown that some individuals already have SARS-CoV-2 specific CD8 + T cells prior to SARS-CoV-2 infection, this is still a minority of individuals (20%) [84]. In all SARS-CoV-2 infected individuals included in our study we found activated KIR + RA +  T cells, indicating bystander activation. Still, caution should be considered with regard to the specificity of these cells and our findings warrant new immune studies to investigate potential antigen-specificity of KIR + RA + T cells. INTERVENING WITH AGE-RELATED CHANGES TO T CELLS VIA MTOR Currently, therapeutic and preventive targeting of age-related events to reduce inflammation is widely being explored, with the ultimate goal to improve the response to vaccination, infection, and a healthy life span. The mammalian target of rapamycin (mTOR) pathway is an important driver of cellular aging [85] and is a well-known target in anti-aging research. For example, blocking of mTOR with rapamycin can expand life- and health span in mice [86-88], can improve the response to influenza vaccination in elderly individuals [89], and can reduce secretion of the SASP, including IL-6 in vitro [90]. In chapter 3 of this thesis, we assessed whether blocking of mTOR by rapamycin could slow down the effect of aging by compromised DNA damage repair on the phenotype and response of T cells. The main conclusion of our study is that the majority of changes in T cells we observed due to compromised DNA damage repair cannot be reversed by inhibition of mTOR activation. For example, we show that the accumulation of Tregs in Ercc1 -/ Δ 7 mice cannot be reversed by rapamycin, but rather promoted these Tregs to express CD25 and PD-1 which may indicate improved immunosuppressive capacity of these cells [91]. However, the decline in proportion of naive T cells and the increase in memory T cells observed in WT 6