Sara van den Berg

205 8 General discussion ( chapter 4 ). Secondly, the dynamics of memory CD8 + T-cells are not substantially affected by CMV infection, while the production and loss rate of memory CD4 + T-cells is lower in CMV+ individuals than CMV- individuals ( chapter 6 ). Third, CMV-specific T-cells express a late-stage differentiation state, and these markers correlate with a decreased production and death rates in vivo , but CMV-specific T-cells do not substantially differ in their in vivo dynamics compared to bulk memory T-cells, as assessed by heavy water labelling ( chapters 5, 6 ). Lastly, we found no evidence that the CMV-induced changes in the T-cell pool and the size of the CMV-specific immune response accumulate to a large extent during long- term CMV infection ( chapter 7 ). Interestingly, older age, regardless of duration of CMV infection, turned out to lead to more prominent CMV-induced changes in the T-cell pool and to larger CMV-specific immune responses ( chapter 7 ), which suggests that high CMV immune responses may be merely a consequence of immunological ageing. DOES CMV IMPAIR IMMUNE RESPONSES TO HETEROLOGOUS INFECTIONS? CMV does not substantially hamper the immune response to influenza The role of CMV infection on heterologous immune challenges in vivo in humans has mainly been investigated for the clinically relevant immune response to influenza. Predominantly negative effects of CMV on the influenza antibody response have been reported [16, 17], but conflicting studies [15, 18] have led to controversy [19]. We observed no significant effect of CMV on the antibody response to influenza vaccination, despite a significant effect of age, when the possible confounder of pre-existing immunity was reduced by studying the response to a pandemic novel vaccine strain ( chapter 2 ). This is in line with a study in a large group of subjects, which reported no effect of CMV infection on the antibody response to influenza vaccination [20]. Our systematic review and meta-analysis of all studies on the association between CMV infection and the antibody response to influenza vaccination in younger and older adults showed that there is no unequivocal evidence for a negative effect of CMV infection ( chapter 3 ). Importantly, CMV mainly affects the T-cell pool, but cellular responses to influenza are investigated less frequently than antibody responses. This is probably due to logistic reasons as influenza vaccines, at least in Europe, primarily induce antibody and not T-cell responses. T-cell responses are however induced by influenza virus infection and play an important role in elimination of the virus and reduction of severity of disease. Therefore, we also studied the effect of CMV infection on the T-cell response to influenza virus infection in older adults. Despite the fact that CMV infection reduced the frequency of memory influenza virus-specific T-cells, it did not affect the T-cell response to acute influenza virus infection. Also, severity of symptoms of influenza virus infection was not increased by CMV infection, suggesting no substantial clinical impact of CMV on influenza virus infection. While others showed a lower activation level of CD8 + T-cells after influenza vaccination in CMV+ compared to CMV- older adults [21], we did not observe this after influenza virus infection ( chapter 4 ). Two other papers investigated the association between CMV and the cellular immune response