Daan Pieren

181 General discussion and future perspectives induction of activation markers on T cells may provide an answer to whether decreased protection against infectious diseases in older adults is caused by impaired activation and proliferative T-cell responses. Throughout this thesis, we report an accumulation of regulatory-cell features in the T-cell population at older age and identify a new aging-related regulatory CD8 + T-cell subset. One prominent question that remains unanswered is whether immunosenescent T cells expressing regulatory properties such as the KIR + RA + T cells we define only act as suppressive cells during viral infection, or whether they also contribute to clearance of virally infected cells. Additionally, it would be of high interest to assess how KIR + RA + T cells as well as other characteristics of immune suppression develop with progressing age and if so, whether this process could be invoked or halted. One of the possibilities to investigate is whether the accumulation of KIR + RA + T cells can be accelerated by pro-inflammatory factors that have been reported to increasingly circulate at older age. Moreover, our research provides new links to potential intervention strategies to target KIR + RA + T cells, such as Helios and TIGIT. Targeting these molecules may provide insight into survival and suppressive mechanisms involved in this CD8 + T-cell subset. Together, these insights may provide new targets for preventive or therapeutic strategies to either block or promote KIR + RA + T cells, not only in the context of aging, but also in the fields of cancer, transplantation, and autoimmunity. CONCLUDING REMARK The search for novel hallmarks of T-cell aging is one of the most important fundamental challenges in the immune aging field. In this thesis, we provide new insights in murine and human T-cell aging which enhances understanding of the impact of aging on T cells. Our findings highlight the importance of studying the altered response kinetics of T cells at older age and the rise of regulatory-cell features in the T-cell population, which both may contribute to impaired protective immunity against infectious diseases in older individuals. Ultimately, these fundamental findings may provide new starting points for other fundamental, translational, and clinical studies that focus on vaccination of older adults, infectious disease resistance, and healthy aging. 6