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Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell Pool Changes Observed in Mice with Aging

Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell Pool Changes Observed in Mice with Aging

Authors :
Lea Haeberli
Urs Karrer
Andrea Mekker
Alexandra Trkola
Annette Oxenius
Vincent S. Tchang
University of Zurich
Karrer, Urs
Source :
PLoS Pathogens, Vol 8, Iss 8, p e1002850 (2012), PLoS Pathogens, PLoS Pathogens, 8 (8)
Publication Year :
2012
Publisher :
Public Library of Science (PLoS), 2012.

Abstract

Immune senescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterised by impaired protective immunity and decreased efficacy of vaccines. Recent clinical, epidemiological and immunological studies suggest that Cytomegalovirus (CMV) infection may be associated with accelerated immune senescence, possibly by restricting the naïve T cell repertoire. However, direct evidence whether and how CMV-infection is implicated in immune senescence is still lacking. In this study, we have investigated whether latent mouse CMV (MCMV) infection with or without thymectomy (Tx) alters antiviral immunity of young and aged mice. After infection with lymphocytic choriomeningitis virus (LCMV) or Vaccinia virus, specific antiviral T cell responses were significantly reduced in old, old MCMV-infected and/or Tx mice compared to young mice. Importantly, control of LCMV replication was more profoundly impaired in aged MCMV-infected mice compared to age-matched MCMV-naïve or young mice. In addition, latent MCMV infection was associated with slightly reduced vaccination efficacy in old Tx mice. In contrast to the prevailing hypothesis of a CMV-mediated restriction of the naïve T cell repertoire, we found similar naïve T cell numbers in MCMV-infected and non-infected mice, whereas ageing and Tx clearly reduced the naïve T cell pool. Instead, MCMV-infection expanded the total CD8+ T cell pool by a massive accumulation of effector memory T cells. Based on these results, we propose a new model of increased competition between CMV-specific memory T cells and any ‘de novo’ immune response in aged individuals. In summary, our results directly demonstrate in a mouse model that latent CMV-infection impairs immunity in old age and propagates immune senescence.<br />Author Summary Cytomegalovirus (CMV) persistently infects 50–90% of the human population. After primary infection, constant immune surveillance is required to prevent CMV-related disease. During ageing, increasing T cell resources are expended to keep CMV under control. Recent human studies have suggested that this investment may come at the cost of accelerated immune senescence, a condition describing the age-associated decline of the immune system's functionality. In the present study, we have developed a mouse model to directly investigate whether and how CMV-infection might impair immunity of aged individuals. We demonstrate that old mice with long-lasting CMV-infection are more susceptible to viral infections than old mice without CMV since their virus specific T cell response is suppressed. Contrary to the prevailing hypothesis we found no indication for a CMV-associated shrinking of the naïve T cell compartment. Instead, CMV-infection precipitated a massive expansion of memory T cells. Thus, we propose an alternative mechanism of CMV-enhanced immune senescence based on T cell competition between CMV-specific memory T cells and de novo generated T cell responses. In summary, we provide the first direct evidence that CMV-infection is indeed a propagating factor for poor immunity in the elderly.

Details

Language :
English
ISSN :
15537374 and 15537366
Volume :
8
Issue :
8
Database :
OpenAIRE
Journal :
PLoS Pathogens
Accession number :
edsair.doi.dedup.....3c1c4afa13027e779a414d3667ca7de8