Sara van den Berg

137 6 T-cell dynamics in CMV ABSTRACT Background: Cytomegalovirus (CMV) infection is known to have a major impact on the T-cell pool, which is typically ascribed to the presence of large numbers of CMV-specific memory CD8 + T-cells. It has been suggested that these CMV-specific CD8 + T-cell populations are established through gradual accumulation of long-lived cells. It remains unknown whether the impact of CMV on the T-cell pool stretches beyond the presence of large numbers of CMV-specific CD8 + T-cells, and whether CMV infection leads to changes in the dynamics of the memory T-cell pool as a whole. Methods: In this study, we aimed to investigate the effect of CMV infection on CD4 + and CD8 + T-cell dynamics in healthy older adults, and to unravel the mechanisms of maintenance of large numbers of CMV-specific CD8 + T-cells. We studied the expression of senescence, proliferation, and apoptosis markers (among others CD57, KLRG-1, and Ki-67) in 22 healthy CMV-seronegative (CMV-) and 32 CMV-seropositive (CMV+) individuals. Additionally, we quantified the in vivo dynamics of different CD4 + and CD8 + memory T-cell populations and specifically of CMV-specific CD8 + T-cells in 5 CMV+ and 5 CMV- individuals by deuterium labelling. Results: The increased expression of late-stage differentiation markers by CD8 + T-cells of CMV+ versus CMV- individuals was not solely explained by the presence of CMV-specific CD8 + T-cells. The average production rates of CMV-specific CD8 + T-cells and of different CD8 + memory T-cell populations in CMV- and CMV+ individuals were not significantly different. CD4 + memory T-cells of CMV+ individuals showed an increased expression of late- stage differentiation markers, decreased Ki-67 expression and a trend towards lower T-cell production rates as assessed by in vivo deuterium labelling compared to CMV- individuals. Overall, the expression of senescence markers correlated negatively with in vivo production rates. Conclusion: Together, this work suggests that i) CMV-specific CD8 + T-cell inflation is not due to a gradual accumulation of long-lived cells, ii) the impact of CMV infection stretches beyond the presence of large numbers of CMV-specific CD8 + T-cells, but iii) CMV infection hardly affects the dynamics of the CD8 + T-cell pool, while it is associated with reduced CD4 + T-cell production rates.