Sara van den Berg

214 Chapter 8 drives exhaustions of T-cells [51]. In mice, it was shown that frequent in vivo boosting of T-cells by sequential antigenic challenge can result in non-exhausted high quality T-cells in cases where the immune system gets enough time to “rest” in between the challenges (‘boosting-with-breaks’) (adoptive transfer mice experiments, David Masopust, conference). Interestingly, multiple boosts with breaks led to a restricted contraction phase after the peak of the T-cell response, thereby yielding high numbers of memory T-cells. We speculate that a process like this may also occur in CMV infection: CMV may just give the immune system the required rest in between reactivation episodes to achieve high numbers of memory T-cells while maintaining their high quality. When the rest period in between sequential challenges was shortened in mice, an exhausted T-cell phenotype was established (David Masopust, conference), a phenomenon that is also seen in humans during chronic infections ( chapter 5 ). Limited contraction after numerous T-cell challenges with in-between-breaks seems applicable to the unique situation of ‘dynamic latency’ in CMV. However, this idea of limited contraction after numerous T-cell challenges including in-between rests, would imply an effect of time on memory CMV-specific T-cell numbers. As discussed above, our results indicate duration of CMV infection does not seem to play a large role in humans. Whether a system of “boosting-with-breaks” is indeed responsible for reduced contraction of T-cell responses to CMV in humans, and might be key in the unique T-cell phenotype and magnitude of the T-cell response, would also be of great interest for further research and will help to further understand the phenomenon of memory inflation in human. A CURRENT VIEW ON CMV AND AGEING OF THE IMMUNE SYSTEM: HIGH CMV-SPECIFIC IMMUNE RESPONSES AS CAUSE OR CONSEQUENCE OF IMMUNOLOGICAL AGEING? A changing mainstream view The mainstream view on the impact of CMV on ageing of the immune system has changed quite a lot over the last couple of years [52, 53]. Associations between CMV infection and impaired immunological health outcomes turned out to be less strong than initially thought, and even positive associations between CMV and health outcomes have been reported. We observed no link between CMV infection and frailty. In fact, the link between CMV infection and increased risk for mortality might to a large extent be due to increased cardiovascular- related death and not due to a direct effect on the immune system. The evidence for CMV- enhanced prevalence of cardiovascular disease and severity of disease seems rather solid [54]. Mechanistically, CMV in endothelial cells is thought to reactivate quite often, causing endothelial dysfunction, which may in turn contribute to the development of atherosclerosis and ischemic heart disease [55]. For immunological clinical outcomes such as the immune response to influenza, no clear evidence pointing into specific mechanisms of CMV as a direct cause is currently available, e.g. for increased pro-inflammatory levels [36] and out competition of T-cells ( Chapter 4 ) . Importantly, more recent longitudinal studies into the role of CMV in the ‘immune risk profile’ could not always reproduce the findings of the original Swedish longitudinal immune risk study [56], which may be partly explained by genetic differences. Taken together, a current model of the association of CMV infection and ageing