Abstract
Prominent immune alterations associated with aging include the loss of naïve T-cell numbers, diversity and function. While genetic contributors and mechanistic details in the aging process have been addressed in multiple studies, the role of environmental agents in immune aging remains incompletely understood. From the standpoint of environmental infectious agents, latent cytomegalovirus (CMV) infection has been associated with an immune risk profile in the elderly humans, yet the cause-effect relationship of this association remains unclear. Here we present direct experimental evidence that mouse CMV (MCMV) infection results in select T-cell subset changes associated with immune aging, namely the increase of relative and absolute counts of CD8 T-cells in the blood, with a decreased representation of the naïve and the increased representation of the effector memory blood CD8 T-cells. Moreover, MCMV infection resulted in significantly weaker CD8 responses to superinfection with Influenza, Human Herpes Virus I or West-Nile-Virus, even 16 months following MCMV infection. These irreversible losses in T-cell function could not be observed in uninfected or in vaccinia virus-infected controls and were not due to the immune-evasive action of MCMV genes. Rather, the CD8 activation in draining lymph nodes upon viral challenge was decreased in MCMV infected mice and the immune response correlated directly to the frequency of the naïve and inversely to that of the effector cells in the blood CD8 pool. Therefore, latent MCMV infection resulted in pronounced changes of the T-cell compartment consistent with impaired naïve T-cell function.
Highlights
Cytomegalovirus (CMV) is a ubiquitous herpesvirus, latently persisting in the majority of the adult human population worldwide [1]
More recent studies raised some doubt on these findings, arguing that not all aging human populations exhibit immune risk profile (IRP) [16], yet others showed a correlation between CMV seropositivity and frailty in the elderly [9,17] or increased mortality [9]
The cytomegalovirus (CMV) is a widespread virus of the herpesvirus family, which latently infects the majority of the adult human population worldwide
Summary
Cytomegalovirus (CMV) is a ubiquitous herpesvirus, latently persisting in the majority of the adult human population worldwide [1]. More recent studies raised some doubt on these findings (for a review see the recent Report from the Second Cytomegalovirus and Immunosenescence Workshop [15]), arguing that not all aging human populations exhibit IRP [16], yet others showed a correlation between CMV seropositivity and frailty in the elderly [9,17] or increased mortality [9]. While the clinical studies could show the association of CMV infection and parameters associated with immune senescence, they cannot elucidate the cause-effect relationship between these phenomena. It was not clear if CMV infection causally contributes to immune senescence or if immune senescence or predisposition for other immune alterations results in an increase of susceptibility to CMV infection
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