Daan Pieren

163 General discussion and future perspectives subsets in vitro stimulated with anti-CD3 and/or anti-CD28 over time and found that upregulation of CD25 and CD69 expression by T cells of aged mice is reduced and delayed compared to young mice. Moreover, proliferation of T cells of aged mice over time after anti-CD3 and/or anti-CD28 stimulation was significantly reduced. Additionally, we found that production of IL-2, a major driver of T-cell proliferation was impaired in aged mice. Supplementation of T-cell cultures with IL-2 did not enhance proliferation of aged T cells, indicating that this pathway of T-cell stimulation is impaired in aged mice. In chapter 3 , we addressed whether reduced and delayed T-cell activation and proliferation could be attributed to compromised DNA repair. In contrast to our findings in chapter 2 , T cells of Ercc1 -/ Δ 7 mice showed minimal impaired induction of CD25 expression nor T-cell proliferation in response to anti-CD3 and/or anti-CD28 stimulation. This at least indicates that compromised DNA repair does not explain reduced T-cell activation we found in aged wild type mice. Interestingly however, the T-cell response of Ercc1 -/ Δ 7 mice to anti-CD3 and supplemented IL-2 showed a trend towards impaired induction of CD25 and impaired proliferation, which was similar to findings in wild type aged mice. These findings led us to conclude that impairment of IL-2-mediated signaling at old age may at least partially be caused by compromised DNA repair, whereas impaired CD28-mediated signaling may not. In chapter 4 we described a new aging-related subset of human CD8 + T cells. These TIGIT + Helios + CD8 + T cells were increasingly present in the blood of older adults and showed reduced induction of CD25 expression, delayed expression of CD69, and diminished proliferation. These findings are similar to the altered response kinetics of CD8 + T cells from aged mice ( chapter 2 ). Altered in vitro response kinetics of CD8 + T cells from aged mice can thus be found in an aging-related subset of human CD8 + T cells and therefore highlights that altered response kinetics is a common aging-related phenomenon. Whether human CD4 + T cells also show comparable response kinetics as found in mice remains to be established. Thus, we conclude that aging slows down the capacity of T cells to express activation markers and to proliferate in response to stimulation. Do slower kinetics of T-cell responses lead to a loss of protective immunity against infectious diseases? An important question that now remains is the in vivo relevance of these findings. During respiratory infectious diseases, expression of CD69 is required for the egress of lymphocytes to the lymph system [7] and the infected lung [8] and therefore plays a role in the continuation of the immune response. 6