Sara van den Berg

210 Chapter 8 specific memory T-cells by CMV infection may be small and restricted to a increased expression level of senescence markers. When expression levels were assessed in our group, no difference in senescence markers for EBV-specific T-cells, but differences in other markers (increased CD45RO and decreased PD-1) were observed in CMV+ individuals compared to CMV- individuals (Lanfermeijer et al, manuscript in preparation). Further research, possibly investigating the expression level of senescence- and memory markers of other antigen- specific T-cells in CMV- and CMV+ individuals, is needed to confirm these CMV-induced changes. Alternatively, non-CMV-specific memory T-cells as a whole can be investigated. Ideally, all CMV-specific T-cells would have to be deleted from the T-cell pool of CMV- infected individuals, to compare the characteristics of the non-CMV specific T-cell pool of CMV-infected individuals with the T-cell pool of CMV- individuals. Taken together, our work ( chapter 6 ) indicates that a part of the CMV-induced changes in the T-cell pool might not be explained by CMV-specific T-cells, but to what extent this is reflected in other-antigen specific T-cells needs further investigation. MEMORY INFLATION: HOW ARE HIGH CMV-SPECIFIC T-CELL NUMBERS ESTABLISHED AND MAINTAINED OVER TIME? Viral reactivation is thought to be key in memory inflation of CMV-specific T-cells In order to understand the potential effect of CMV on the immune system, we need to know whether memory CMV-specific T-cell responses increase over time in humans (‘memory inflation’). A lot of the knowledge about memory inflation was gained from mouse studies, which reported memory inflation predominantly for CD8 + CMV-specific T-cells, and sometimes also for CD4 + CMV-specific T-cells. In humans, high CMV-specific T-cell responses have been shown to be associated with older age in cross sectional studies [30]. It is generally assumed that continuous TCR triggering by antigen presentation is key in the maintenance of high numbers of CMV-specific T-cells. CMV expresses latency-associated genes during latent infection, but the large T-cell responses against CMV are mainly directed against lytic-expressed genes. Viral reactivation is expected to lead to antigen presentation to CMV-specific T-cells, regardless of production of full virus particles and viral dissemination. This way, the number of CMV-specific T-cells is thought to increase in time. An increased number of CMV-specific T-cell numbers might depend on the recruitment of more CMV- specific memory T-cells after TCR-triggering. Production of CMV-specific memory T-cells may probably be mostly due to proliferation of CMV-specific memory T-cells by TCR-triggering of existing memory CMV-specific T-cells, clonal expansion and limited contraction to form memory T-cells. Thereby, this would lead to an increase of CMV-specific T-cell number over time. In this case, increased proliferation in CMV-specific T-cells would be the underlying mechanism of the high CMV-specific T-cells numbers. Alternatively, the increase of CMV- specific T-cell number might be explained by accumulation of cells having an extended lifespan, possibly by an increased resistance for apoptosis. This effect can be especially large when not only homeostatic proliferation, but also antigen stimulation results in production of memory CMV-specific T-cells. If these are long-lived (having a lower loss rate than production