Daan Pieren

11 General introduction and scope of this thesis the tightly regulated system out of balance. The age-related changes to the immune system have collectively been termed ‘immunosenescence’ [22]. As a consequence of immunosenescence, the effectivity of the immune system to respond and protect against pathogens declines and thereby the susceptibility to infectious diseases and disease severity increase [22]. As life-expectancy and the elderly population continues to grow, detailed insight into what happens to the immune system with age is key to understand susceptibility to disease in older adults. These fundamental insights may eventually be starting points to develop preventive strategies against infectious diseases, including vaccination, as well as to reduce the burden of disease in the elderly with the final goal to increase the amount of life years spent in good health. THE IMMUNE SYSTEM: T CELLS DURING VACCINATION AND INFECTION The immune system consists of two arms: the innate immune system and the adaptive immune system. These two arms work in concert, complement each other, and require each other to exert their optimal function and to achieve optimal protection. When a pathogen is encountered for the first time, innate immune cells are triggered and specialized antigen presenting cells (APCs) take up (parts of) the pathogen. These APCs then migrate to the lymph node and present parts of the pathogen to the adaptive immune system, of which T lymphocytes (T cells) and B lymphocytes (B cells) are critical mediators [23]. T cells can roughly be divided into two subsets: CD4 + T cells and CD8 + T cells. Part of the CD4 + T-cell population has been named ‘helper T cells’ as it has been shown that they interact with dendritic cells to improve the quality of a protective CD8 + T-cell response against virus infected cells and tumors, as well as providing help to B cells for the production of antibodies [24,25]. Additionally, CD4 + T cells can also limit disease severity after experimental influenza infection in humans, indicating a direct anti-viral role for these cells [26]. CD8 + T cells are generally regarded as a T-cell subset that is capable of eliminating intracellular pathogens by killing infected cells through their cytotoxic capacity [23]. The cytotoxic capacity of CD8 + T cells to kill infected cells is mediated by secretion of perforins and granzymes [27,28] and secretion of interferon- γ (IFN- γ ) to enhance viral clearance [23]. The protective role of CD8 + T cells has been shown in mice infected with RSV [29,30], as well as in experimentally RSV- and Influenza-virus infected humans [31,32]. During a primary response, interaction of APCs with naive T cells initiates proliferation, activation, and differentiation of 1