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

PLoS Pathog. 2021 Dec 16;17(12):e1010152. doi: 10.1371/journal.ppat.1010152. eCollection 2021 Dec.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / virology
  • Female
  • Humans
  • Immunologic Memory / immunology*
  • Latent Infection / immunology*
  • Latent Infection / virology
  • Male
  • Middle Aged

Grants and funding

This research was (partially) funded by the Netherlands Organisation for Scientific Research (NWO) Science domain NWO-ENW, project ALWOP.512 (https://www.nwo.nl/en/science-enw) (to JAMB), and the Strategic Program Research (SPR) of the National Institute of Public Health and the Environment (RIVM) (https://www.rivm.nl/en/about-rivm/mission-and-strategy/our-work/tasks/knowledge-development-and-research/strategic-research-0) (to DB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.