Sara van den Berg

207 8 General discussion MAJOR HYPOTHESIS ON THE MECHANISM OF CMV-ENHANCED AGEING HAS LOST SUPPORT Competition for ‘limited immunological space’ between the large numbers of CMV-specific T-cells and other antigen-specific T-cells has been proposed as a main explanation for the negative impact of CMV by several researchers [27-29]. In fact only a handful of studies report data supporting this view. In support of this view, Epstein-Barr virus-specific T-cells were found to be decreased in frequency and absolute number in CMV+ compared to CMV- older adults [30]. Influenza T-cell frequencies ( chapter 4 ) or responses [22]were found to be decreased in CMV-infected individuals in some studies, but not in others [23]. It is important to realize that decreased frequencies of influenza virus specific T-cells or T-cell responses in CMV-infected individuals do not necessarily imply that influenza-specific T-cell numbers are also reduced. CMV-specific T-cell numbers can become very large and may thereby reduce the frequency of other T-cell specificities ( chapter 4 ) [22]). In fact, there is no convincing evidence for loss of memory T-cells in CMV+ individuals due to competition for homeostatic growth or survival factors, also referred to as passive memory attrition, in humans. We also found no evidence for reduced T-cell production rates or increased T-cell death rates in vivo in CMV+ individuals ( chapter 6 ), thereby contradicting the theory of continuous recruitment of new CMV-specific T-cells in to the memory pool thereby actively pushing out pre-existing memory T-cells specific for influenza (a.o.), also referred to as ‘active memory attrition’ [31, 32]. Furthermore, the presence of high CMV-specific T-cells numbers is typically assessed in the blood, reflecting only about 2% of the total T-cell population in the body, which might not be representative for the total number of T-cells. Large numbers of CMV-specific T-cells were shown to be present outside the blood as well, e.g. in bone marrow, lymph nodes as well as in other organs [33], although others reported only high numbers of CMV-specific T-cells in blood and not in lymph nodes [34]. We believe that the immune system might, especially during acute infections, be flexible in ‘space’ in order to host clonal expansions of T-cells to combat infections. Indeed, we found that large CMV-specific T-cell responses in CMV+ older individuals did not hamper the T-cell response to acute influenza virus infection ( chapter 4 ). The other major hypothesis on how CMV could impact the function of the immune system, is through the induction of pro-inflammatory cytokines. These pro-inflammatory cytokines may in turn influence other immune challenges as a bystander effect, for example through the induction of TNF α , IL-6 or high granzyme B levels. In mice, CMV-induced IL-6 production was shown to reduce the number of bystander memory T-cells and affects the subsequent immune response to a heterologous challenge [35]. However, we observed no association between CMV and pro-inflammatory cytokine levels in humans ( chapter 4 ). In line with this, a longitudinal study over 10 years also showed that CMV infection was not associated with a steeper increase in pro-inflammatory cytokine levels[36]. In theory, influenza antibody responses may also be hampered by CMV infection through reduced CD4 + T-helper cell responses, thereby hampering the antibody production of B-cells. In mice, it was recently shown that CMV infection led to delayed B-cell class switching, which impaired the peak