Abstract
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.
Highlights
In an ongoing fight against new and emerging viruses and bacteria, the adaptive immune system provides a unique line of defence for its host
CMV is 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
Summary
In an ongoing fight against new and emerging viruses and bacteria, the adaptive immune system provides a unique line of defence for its host. Adaptive immunity is highly specific against pathogens, it enables protection for many years. Immunological memory requires long-term maintenance of T-cell memory. After an infection is cleared, the pool of generated effector memory (TEM) and central memory (TCM) T-cells typically contracts, and a small population of antigen-specific T-cells is maintained over time. It is challenging to measure the lifespan of cell populations in vivo in humans, it is important to obtain such quantitative insights in order to understand how T-cell memory is maintained. Several features of the T-cell compartment can be severely impacted by chronic viral infections, by human cytomegalovirus (CMV), which need to be taken into account
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