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

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. Author summary: Most 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. [ABSTRACT FROM AUTHOR]