Daan Pieren

20 Chapter 1 AIM AND SCOPE OF THIS THESIS T cells are imperative for protection against pathogens and various molecules on different subsets of T cells are involved in maintaining a balanced immune system. T cells express molecules that initiate cellular activation and proliferation, but there are also molecules that act as a breaking mechanism on these responses to prevent over-activation. During aging, this system becomes dysregulated. To explain reduced response to vaccination, susceptibility to infectious disease, and increased disease severity observed at older age, it is crucial to identify the underlying age-related changes of T cells. In this thesis, we set out to identify novel age-related changes of the T-cell population in mice and humans that may contribute to understanding the impact of aging on T cells. We investigate T-cell phenotype, responses, and proliferation in both mice and humans under healthy conditions and during respiratory viral infection in humans. The kinetics of a T-cell response (i.e. T-cell activation and proliferation over time after stimulation) are often overlooked in literature. However, proliferation and activation kinetics of a T-cell response may precisely be the factors that determine the outcome of an immune response. In chapter 2 of this thesis, we investigate the impact of aging on the phenotype of CD4 + and CD8 + T cells and their responsiveness to stimulation over time. Our findings on alterations of T-cell response kinetics as a consequence of aging may serve as a new hallmark of T-cell aging and contribute to understanding the reduced response of T cells after vaccination or infection. One of the most important hallmarks of aging in many organisms is the accumulation of DNA damage over a lifetime. Accumulation of DNA damage within the nucleus of a cell causes the cell to become senescent. However, the impact of DNA damage on T cells during aging is not fully known. In chapter 3 , we investigate the impact of compromised repair of DNA damage on the phenotype and responsiveness of T cells by using a specific mouse model for cellular senescence. Mice that have a deficiency in one of the DNA repair genes ( Ercc1 ) show compromised DNA repair and therefore accumulate DNA damage. The Ercc1 mouse model enables the investigation of senescent cellular environment on T cells that reside in this environment. In this chapter, we use the Ercc1 mouse model to study the effect of compromised DNA repair on T-cell phenotype and responsiveness. Chapters 4 and 5 of this thesis address the impact of aging on CD8 + T cells in humans. In chapter 4 , we aimed to improve the insight into the progression of immunosenescence in human CD8 + T cells. We addressed this aim by