Daan Pieren

179 General discussion and future perspectives First, increased and sustained expression of co-inhibitory markers by T cells is a widely reported observation to occur during aging and is often approached as disadvantageous. However, this appears to be more subtle. A study that strikingly illustrates the importance of the co-inhibitory marker PD-1 has shown that genetically disrupting expression of PD-1 leads to overstimulation and severe exhaustion of anti-viral T cells [95]. This study led to the hypothesis that the PD-1 inhibitory pathway, as well as those of other co-inhibitory receptors may have evolved to prevent excessive damage induced by persistent infections by limiting T-cell function. These findings may therefore also highlight the importance of TIGIT + CD8 +  T cells we observe at older age ( chapters 4 and 5 ). Besides that TIGIT + CD8 + T cells mark a subset of regulatory T cells ( chapter 5 ), we also observe sustained expression of TIGIT on other CD8 + T cells, that are considered to be exhausted [49]. Possibly, sustained expression of TIGIT on these cells may promote their survival by preventing over-stimulation of these cells, and may also limit pathology following viral infection [81]. By this way, these cells survive, can still act as cells that protect against infectious disease, as well as reducing the collateral immune pathology done to the host. Second, in this thesis we focus on aging of T cells in an infectious disease setting. Broadening interpretation of hallmarks of immunosenescence from the fields of tumor immunology and autoimmunity however, can further improve our insight and even shows potential benefits of cellular exhaustion. A recent study has strikingly shown that CD8 + T cells with features of exhaustion indeed associate with poor clearance of viral infection, but on the other hand these cells predicted a better prognosis in several autoimmune diseases [96]. Additionally, the field of tumor immunology taught many lessons on exhaustion and senescence, and co-inhibitory receptors are often blocked to elicit anti- tumor responses. However, these therapies may also induce a break of self- tolerance, resulting in autoimmune disease [97]. Thus, taking these views into account, targeting of exhaustion and senescence related markers on T cells in the context of aging and infectious disease should aim for achieving a delicate balance between the T-cell response against infectious diseases and tumors, whilst not breaking tolerance to prevent autoimmune disease ( Figure 5 ). 6