Daan Pieren

15 General introduction and scope of this thesis Figure 1. Potential consequences of the accumulation of regulatory T cells during aging. Schematic representation of a primary viral infection and part of the subsequent immune response at young and old age. After viral infection, antigen-presenting cells (APCs) present part of the pathogen to naive T cells within the lymph node. At younger age, naive T cells differentiate into effector T cells, which in turn expand by cellular proliferation. Effector T cells then target virus-infected cells and kill these cells, resulting in apoptosis of the virally infected cell to limit viral dissemination. Moreover, during these responses in young individuals, regulatory T cells (Tregs) maintain homeostasis by interfering at multiple steps in this process to prevent immunopathology. Tregs may limit APC-naive T-cell interactions, limit effector cell proliferation, and limit effector cell-mediated killing. However at old age, Tregs have accumulated and are therefore much more potent at dampening the three aforementioned steps towards killing of the infected cell. Suppression of killing may therefore result in viral dissemination, leading to more infected cells and prolonged and/or more severe disease. T-cell Senescence Outside of the field of immunology, cellular senescence is used to describe a state of cells that are irreversibly stuck in their cell cycle and do not proliferate anymore due to irreparable cell damage [83]. By preventing proliferation of damaged cells, cellular senescence is viewed as a process that prevents or limits tumor growth [84]. One of the hallmarks that drives cellular senescence is the intracellular accumulation of DNA damage [83]. Senescent cells are known to slowly accumulate over a lifetime [85]. These cells have popularly been termed ‘zombie cells’, as it has been shown that these cells accumulate with age in a variety of organs, do not divide, nor undergo apoptosis [86]. However, these 1