Elsevier

Virus Research

Volume 157, Issue 2, May 2011, Pages 175-179
Virus Research

Role of CMV in immune senescence

https://doi.org/10.1016/j.virusres.2010.09.010Get rights and content

Abstract

“Immune senescence” is a descriptive term for the deleterious age-associated changes to immunity observed in all mammals studied so far. While all components of innate and adaptive immunity are changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenescence are controversial. In humans, several cross-sectional studies have demonstrated that the major accepted age-associated changes to parameters used to assess adaptive immune status are markedly influenced by infection with cytomegalovirus (CMV). In the very limited longitudinal studies thus far carried out, a cluster of immune parameters associating with 2-, 4- and 6-year survival of the very elderly has been identified and termed the “immune risk profile” (IRP). This cluster includes seropositivity for CMV and is characterised by accumulations of clonal expansions of late-differentiated CD8+ T cells, many of which are specific for CMV antigens. Here we review the impact of CMV on “immune senescence” in humans.

Introduction

In the industrialised nations, death rates from infectious disease accelerate with age but unlike classical age-associated diseases (cardiovascular, cancer) this acceleration seems not to plateau in late life, but to continue to accelerate (Horiuchi and Wilmoth, 1997). Thus, the chance of dying of an infection in very old age continues to increase up to the maximum lifespan achievable. Because immunity evolved to protect against pathogens, it is likely that immunosenescence is one of the reasons for the increased sensitivity and susceptibility of the elderly to infectious disease. As long as 3–4 decades ago, researchers have sought age-associated alterations to immune parameters and tried to establish correlations between these changes and clinical outcome or mortality (Murasko et al., 1987, Roberts-Thomson et al., 1974, Wayne et al., 1990). These early studies had proposed that the level of in vitro responsiveness of T cells to mitogens predicted longevity; later, the level of natural killing at baseline was also implicated as correlated with susceptibility to infectious disease in later life (Ogata et al., 2001). Increased levels of inflammatory indicators such as the cytokine interleukin 6 (IL 6) and especially tumor necrosis factor-α (TNF) have also been associated with frailty and compromised survival (Bruunsgaard and Pedersen, 2003, Cohen et al., 2003). Many other age-associated changes to immune parameters have been reported, but correlations with health and longevity have mostly only been proposed, not tested, because the studies have been almost entirely based on cross-sectional approaches. However, such studies fail to compare like with like because young and old groups studied at the same time clearly differ in many important but undefined ways, for example, in pathogen exposure, developmental and nutritional factors, population genetics and many others. Longitudinal studies of the same individuals would overcome this problem, but are clearly challenging in humans. One approach along these lines has been to study populations already advanced in years, so that mortality at follow-up can be compared with measured parameters within a reasonable time frame (Wikby et al., 1994). The rationale is that provided informative factors can be identified in the very elderly, it can be tested whether they are also informative in younger people. In this contribution to the special issue, we will first review data from the Swedish longitudinal OCTO/NONA-immune studies and then consider how these may apply to other populations.

Section snippets

The immune risk profile (IRP) and CMV infection

The OCTO longitudinal studies carried out by the Institute of Gerontology in Jönköping, Sweden focussed on free-living people > 85 years of age selected for extremely good health according to slightly modified SENIEUR criteria (Ferguson et al., 1995). Several waves of recruitment yielded baseline data on many health parameters including, unusually at that time in such studies, some immune parameters (Wikby et al., 1998). In contrast to the exceptionally healthy OCTO subjects, the NONA

Impact of CMV on immune signatures

Studies have documented that the major difference between elderly OCTO/NONA subjects in the IRP group was in the accumulation of CD8+ late differentiated cells (defined by lack of both costimulatory receptors CD27 and CD28). The absolute number of these cells per microliter of blood was markedly increased, as well as their percentage within all CD8+ cells (Pawelec et al., 2005). In contrast, there was no difference between the IRP and non-IRP groups for other CD8 memory cells (as defined by

CMV as a risk factor for mortality

The above results would suggest that CMV drives immune ageing processes that are associated with mortality. Therefore, CMV infection by itself might be predicted to have some impact on survival. Surveys are beginning to suggest that CMV infection may indeed be associated with an increased risk of all-cause mortality. In longitudinal studies of CMV-seropositives, antibody levels have been reported to correlate inversely with survival in people with stable cardiovascular disease (Strandberg et

Would it be beneficial to eradicate CMV?

Given the above considerations, it would appear that the answer to whether CMV should be eradicated would be an unequivocal “yes”. However, it is also conceivable that infection with CMV might convey some advantage in early life, or might have done so in the evolutionary past when infectious disease was a major killer of the young. Infection with CMV is associated with higher background levels of inflammatory mediators which might be protective. There may be an analogy here with a murine model

Acknowledgements

The authors’ own work discussed in this contribution was most recently supported by DFG PA 361/14-1; part of the immunological analysis in the OCTO/NONA studies was supported by the European Commission (T-CIA, contract QLK6-2001-02283).

References (59)

  • Q. Ouyang et al.

    An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein-Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness

    Mech. Ageing Dev.

    (2003)
  • I.C. Roberts-Thomson et al.

    Ageing, immune response, and mortality

    Lancet

    (1974)
  • L. Simonsen et al.

    Mortality benefits of influenza vaccination in elderly people: an ongoing controversy

    Lancet Infect. Dis.

    (2007)
  • R.P. Stowe et al.

    Chronic herpesvirus reactivation occurs in aging

    Exp. Gerontol.

    (2007)
  • P. Trzonkowski et al.

    Immunosenescence increases the rate of acceptance of kidney allotransplants in elderly recipients through exhaustion of CD4+ T-cells

    Mech. Ageing Dev.

    (2010)
  • P. Trzonkowski et al.

    Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients

    Brain Behav. Immun.

    (2004)
  • P. Trzonkowski et al.

    Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination—an impact of immunosenescence

    Vaccine

    (2003)
  • R. Vescovini et al.

    Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells

    Exp. Gerontol.

    (2004)
  • A. Waterstrat et al.

    Effects of aging on hematopoietic stem and progenitor cells

    Curr. Opin. Immunol.

    (2009)
  • A. Wikby et al.

    Age-related changes in immune parameters in a very old population of Swedish people: a longitudinal study

    Exp. Gerontol.

    (1994)
  • A. Wikby et al.

    Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study

    Mech. Ageing Dev.

    (1998)
  • G. Almanzar et al.

    Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons

    J. Virol.

    (2005)
  • V. Appay et al.

    Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections

    Nat. Med.

    (2002)
  • E.S. Barton et al.

    Herpesvirus latency confers symbiotic protection from bacterial infection

    Nature

    (2007)
  • G. Chan et al.

    Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage

    J. Immunol.

    (2008)
  • S. Chidrawar et al.

    Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals

    Clin. Exp. Immunol.

    (2009)
  • L. Couzi et al.

    Cytomegalovirus-induced gammadelta T cells associate with reduced cancer risk after kidney transplantation

    J. Am. Soc. Nephrol.

    (2010)
  • J. Dechanet et al.

    Implication of gammadelta T cells in the human immune response to cytomegalovirus

    J. Clin. Invest.

    (1999)
  • R.B. Effros et al.

    The role of CD8+ T-cell replicative senescence in human aging

    Immunol. Rev.

    (2005)
  • Cited by (0)

    View full text