Quantification of T-cell dynamics during latent cytomegalovirus infection in humans

Author summaryMost people are infected with cytomegalovirus (CMV). Once infected, CMV stays in our body for the rest of our life. It rarely causes severe disease, thanks to T-cells that keep the virus at bay. CMV induces exceptionally large T-cell numbers. While typically no more than 1% of our T-cells recognize a certain virus, for CMV this can be as much as 50%. CMV is therefore used in vaccines to induce high T-cell numbers to other viruses or bacteria. A possible downside of CMV is that it is thought to lead to faster ageing of the immune system. We have studied whether the exceptionally large number of CMV-specific T-cells is due to a lack of cell death of these cells, and whether CMV infection affects T-cells to other viruses. We found that the changes in the T-cell pool of CMV-infected individuals cannot be explained by the presence of large numbers of CMV-specific T-cells. This suggests that CMV infection may also affect T-cells specific for other viruses. We also found that CMV-specific T-cells live as long as T-cells specific for other viruses. These insights are important for our understanding of the effects of CMV infection and for the development of CMV-based vaccines. Cytomegalovirus (CMV) infection has a major impact on the T-cell pool, which is thought to be associated with ageing of the immune system. The effect on the T-cell pool has been interpreted as an effect of CMV on non-CMV specific T-cells. However, it remains unclear whether the effect of CMV could simply be explained by the presence of large, immunodominant, CMV-specific memory CD8(+) T-cell populations. These have been suggested to establish through gradual accumulation of long-lived cells. However, little is known about their maintenance. We investigated the effect of CMV infection on T-cell dynamics in healthy older adults, and aimed 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 and quantified the in vivo dynamics of CMV-specific and other memory T-cell populations using in vivo deuterium labelling. Increased expression of late-stage differentiation markers by CD8(+) T-cells of CMV+ versus CMV- individuals was not solely explained by the presence of large, immunodominant CMV-specific CD8(+) T-cell populations. The lifespans of circulating CMV-specific CD8(+) T-cells did not differ significantly from those of bulk memory CD8(+) T-cells, and the lifespans of bulk memory CD8(+) T-cells did not differ significantly between CMV- and CMV+ individuals. Memory CD4(+) T-cells of CMV+ individuals showed increased expression of late-stage differentiation markers and decreased Ki-67 expression. Overall, the expression of senescence markers on T-cell populations correlated positively with their expected in vivo lifespan. Together, this work suggests that i) large, immunodominant CMV-specific CD8(+) T-cell populations do not explain the phenotypical differences between CMV+ and CMV- individuals, ii) CMV infection hardly affects the dynamics of the T-cell pool, and iii) large numbers of CMV-specific CD8(+) T-cells are not due to longer lifespans of these cells.