Sara van den Berg

16 Chapter 1 even suggest that there might be a beneficial effect of latent CMV infection on the protection rate (titer≥40) after novel influenza vaccination against this novel influenza strain. Since the conclusion of chapter 2 seems to contradict the general view in the literature, in chapter 3 we performed a systematic review and meta-analysis on the effect of latent CMV infection on the antibody response to influenza vaccination. Our primary outcome reveals no clear evidence for an effect of CMV-seropositivity on the influenza vaccine response in young or old individuals. We also found evidence for a publication bias in the literature favouring publications that report a negative effect of CMV. In combination with chapter 2, this work supports the view that CMV infection may not directly form a threat for influenza vaccine responses in older adults. As the effect of CMV on the immune system is most prominent for T-cells, in chapter 4 we study the effect of CMV on the CD8 + T-cell pool . We studied the hypothesis that CMV-induced immunosenescence affects the T-cell response to influenza virus infection in older adults, either through competition for ‘limited immunological space’ or by the induction of a chronic low grade inflammation-state. A large cohort of influenza-infected individuals was analysed for CMV-specific antibodies and T-cells, influenza T-cell responses, cytokine levels and severity of symptoms. Our results question the impact of CMV-induced immunosenescence on the immune response to influenza virus infection. PART II: CMV-INDUCED CHANGES OF THE T-CELL POOL IN OLDER ADULTS Part II of this thesis aims at gaining insights into CMV-specific memory T-cells. Chapter 5 reviews the hallmarks of CMV-specific T-cell differentiation. We study whether the phenotype of CMV-specific CD8 + T-cells is unique in comparison to T-cell responses to other chronic viruses. We also discuss the possible impact of antigen exposure and aging on the advanced differentiation state of CMV-specific CD8 + T-cells. We conclude that the increased presence of the late-stage differentiated effector memory (T EM ) T-cell state is a rather unique feature of CMV infection. A unique phenomenon of CMV-specific T-cells is their maintenance at high numbers for long periods of time. We wondered whether this requires altered dynamics in terms of production and loss rates of these T-cells. In chapter 6 we investigate the underlying cellular dynamics that maintain CMV-specific T-cells, and compare the dynamics of the total CD4 + and CD8 + T-cell pool in CMV- and CMV+ older adults. We assessed this by investigating the expression of senescence, proliferation and apoptosis markers, as well as by an in vivo deuterium labelling study in CMV- and CMV+ older adults to deduce the production and loss rates of T-cells in vivo . We find that both CMV-specific T-cells and the total CD4 + and CD8 + T-cell pools in CMV+ individuals tend to express a late-stage differentiated phenotype. This phenotype is associated with reduced production and loss rates. Nevertheless, CMV