Sara van den Berg

204 Chapter 8 CMV-ENHANCED AGEING OF THE IMMUNE SYSTEM In the early 2000s, it was first suggested that CMV may be a driving force of immunological ageing, as many hallmarks of the T-cell pool observed in older individuals were also observed in individuals with CMV infection. The life-long control of infection with CMV drives exceptionally large T-cell responses, which may even increase with age. This is thought to lead to overcrowding or exhaustion of resources of the immune system. Mechanistically, this was suggested to be due to out-competition of non-CMV-specific T-cells. Alternatively, or additionally, CMV was suggested to induce a chronic sub‐clinical systemic inflammatory state, which gets even more pronounced in older adults and is associated with impaired health outcomes. In line with this, CMV was identified as part of the ‘immune risk profile’ for mortality [1, 2]. Either way, it is thought that duration of CMV infection and the number of experienced viral reactivations of CMV define the size of the CMV effect on the immune system. In mouse models, long-term infection with mouse CMV (MCMV) was indeed shown to hamper the T-cell response to heterologous infections [3, 4]. Cross-sectional studies in humans also supported the view that the immune response to CMV increases with age [5-7], and the first studies into the clinical consequences of CMV infection suggested a decreased immune response to influenza vaccination in CMV-infected individuals [8, 9]. Lastly, large cohorts showed an overall increased mortality risk in CMV-infected individuals [10, 11] and in individuals with higher CMV-specific antibody levels [11-13]. CMV, a previously seemingly harmless virus for healthy individuals, suddenly did not seem so harmless anymore, and might actually have major consequences for health and even reduce people’s life expectancy. The intuitively logical theory of CMV-enhanced ageing of the immune system quickly became firmly established. However, “if it quacks like a duck, it is not always a duck”, and several key questions remained to be investigated about the CMV-enhanced ageing theory. First, in contrast to the observations in mouse models that CMV leads to impaired immune responses to heterologous infections [3, 4, 14], evidence in humans turned out to be much less solid. Some recent studies even revealed a positive association between CMV infection and the immune response to influenza [15]. This raises the following questions: does CMV really impair immune responses to heterologous infections in humans and is this clinically relevant? Could CMV infection even be beneficial for the immune response to heterologous infections? In addition, one may wonder what would be the mechanism of such effects of CMV . To answer these questions we need better insights into the generation and maintenance of the CMV-specific immune response and the way CMV infection impacts the total T-cell pool. Are high CMV-specific T-cell numbers established over time? How are CMV-specific T-cell responses maintained at such high numbers? Are the large effects of CMV on the T-cell pool detrimental? Answers to these key questions are crucial to understand the effects of life-long CMV infection on the immune system. They are needed to identify the potential threat of CMV on public health. This thesis attempts to contribute to these questions and reports 4 main findings. First, the immune response to influenza vaccination ( chapters 2,3 ) and influenza infection ( chapter 4 ) is not impaired by CMV infection, and we found no evidence that CMV infection leads to increased competition between T-cells or increased inflammation levels