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Toll-like receptor 4 (TLR-4) plays a crucial role in the pathophysiology of several age-related diseases. Although poorer function of circulating myeloid dendritic cells (mDCs) has been reported in the elderly, data on TLR-4 function in these cells in older people are lacking. Here, we investigated TLR-4 functionality in the elderly by ex vivo analysis of cytokine production of mDCs in response to LPS in 39 younger (23-34 years) and 61 older (62-77 years) healthy people using flow cytometry. We matched these subjects for Cytomegalovirus (CMV)-serostatus because a latent infection with this ubiquitous herpesvirus is known to affect numerous immune parameters. We found that TLR-4-dependent production of IL-6 and TNF was strongly stimulated in circulating mDCs from the elderly. However, mDCs of more than half of the young donors failed to respond in the same way. This was related to their already highly activated ex vivo state, predominantly observed in CMV-seropositive young donors and associated with lower CMV-specific IgG titres. This may reflect an increasingly important requirement for control of CMV infection throughout life. These data suggest that TLR-4 agonists may be the adjuvants of choice for elderly people, most of whom are CMV-positive, and whose responses to immunization are frequently impaired., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Socioeconomic disadvantage may contribute to poor health through immune-related biological mechanisms. We examined the associations between socioeconomic status, as measured by annual household income, and T-cell markers of aging, including the ratios of CD4 and CD8 effector cells to naïve cells (E/N ratio) and the CD4/CD8 T-cell ratio. We hypothesized that participants with a lower income would have higher E/N ratios and lower CD4/CD8 ratios compared with participants with a higher income, and that these associations would be partially mediated by elevated cytomegalovirus (CMV) IgG antibody levels, a virus implicated in aging and clonal expansion of T cells., Methods: Data were from 79 individuals who participated in the population-based Detroit Neighborhood Health Study. We used linear regression to quantify the association between a $10,000 decrease in income and each ratio outcome., Results: After adjustment for age, sex, race, smoking, medication use, and lifetime history of mental health conditions, lower income was associated with a 0.41 (95% confidence interval = 0.09-0.72) log-unit increase in the CD4 E/N ratio and a 0.20 (95% confidence interval = 0.02-0.39) log-unit increase in the CD8 E/N ratio. CMV immunoglobulin G antibody level partially mediated these associations., Conclusions: Our study suggests that low socioeconomic status is associated with immunological aging as measured by the E/N ratio and that impaired immune control of CMV may partially mediate these associations.

Advancing age is characterized by functional and phenotypic alterations in the distribution of circulating T-cell subsets, some of which are exacerbated by a latent infection with the persistent herpesvirus, cytomegalovirus (CMV). The influence of age, sex and CMV-infection on T-cell subpopulations in the peripheral blood remains incompletely understood. Here, T cells from 157 participants of the Berlin Aging Study II (BASE-II) were characterized at 21-34 (n = 59) and 62-85 (n = 98) years of age. We found that the frequency of naïve CD8(+) T cells was significantly lower in the older group than in the young, and was different in men and women. Elderly men had a significantly lower proportion of naïve CD8(+) T cells than younger men, regardless of their CMV-status, but in older women, this was seen only in the CMV-seropositive group. Reciprocally, older men had a higher proportion of late-differentiated, potentially "senescent" CD57(+) T cells. Thus, T-cell senescence may be more pronounced in older men than women. Within the CD4(+) population, in the elderly of both sexes there was a significantly higher proportion of late-differentiated TEMRA cells (T effector memory cells re-expressing CD45RA), but these were present exclusively in CMV-positive subjects. Finally, for the first time, we examined the so-called TSCM cell (T-stem cell-like memory) subpopulations in both CD4(+) and CD8(+) subsets and found that neither CMV-seropositivity nor age or sex affected their frequencies. This study confirms significant cross-sectional age-associated differences of T-cell subset distribution in a representative German urban population and emphasizes the impact of both sex and CMV-infection on T-cell naïve and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells.

A subset of older people is at increased risk of hospitalization and dependency. Emerging evidence suggests that immunosenescence reflected by an inverted CD4:8 ratio and cytomegalovirus (CMV) seropositivity plays an important role in the pathophysiology of functional decline. Nevertheless, the relation between CD4:8 ratio and functional outcome has rarely been investigated. Here, CD4:8 ratio and T-cell phenotypes of 235 community-dwelling persons aged ≥81.5 years in the BELFRAIL study and 25 younger persons (mean age 28.5 years) were analyzed using polychromatic flow cytometry. In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV. This underscores the notion that in very elderly people, not merely CMV infection but also the state of its accompanying immune dysregulation is of crucial importance with regard to physical impairment., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Influenza remains a major pathogen in older people. Infection with CMV and the accumulation of late-differentiated T cells associated with it have been implicated in poor Ab responsiveness to influenza vaccination in the elderly, most of whom are CMV positive. However, whether CMV infection also affects memory T cell responses to influenza remains unknown. To investigate this, we assessed T cell responses to influenza A matrix protein and nucleoprotein ex vivo in 166 Dutch individuals (mean age 62.2 y, range 42-82) and validated the results in a second cohort from North America (mean age 73.1 y, range 65-81, n = 28). We found that less than half of the CMV-infected older subjects mounted a CD4 T cell response to influenza Ags, whereas ∼80% of uninfected elderly did so. A similar proportion of younger subjects possessed influenza A virus-responsive CD4 T cells, and, interestingly, this was the case whether they were CMV-infected. Thus, the effect of CMV was only seen in the older donors, who may have been exposed to the virus for decades. The percentage of donors with CD8 responses to influenza A virus was lower than those with CD4; this was not influenced by whether the subjects were CMV seropositive or seronegative. CMV-seropositive responders had significantly higher frequencies of late-differentiated CD4 T-cells (CD45RA(+/-)CCR7(-)CD27(-)CD28(-)) compared with CMV-infected nonresponders. These data add to the accumulating evidence that infection with CMV has profound but heterogeneous effects on responses to the products of other viruses and have implications for the design of influenza vaccines, especially in the elderly., (Copyright © 2014 by The American Association of Immunologists, Inc.)

The low percentages of naïve T cells commonly observed in elderly people are thought to be causally associated with mortality, primarily from infectious disease, and are taken as a hallmark of "immunosenescence". Whether low levels of naive cells actually do associate with mortality has, however, not been tested in longitudinal studies. Here, we present correlations between peripheral T-cell phenotypes and 8-year survival in individuals from the population-based prospective Leiden 85-plus Study. Counter-intuitively, we found that a lower frequency of naïve CD8+ T cells (characterized as CD45RA+CCR7+CD27+CD28+) at baseline (>88 years) correlated with significantly better survival, while there was a tendency for the reciprocal accumulation of late-differentiated effector memory cells (CD45RA-CCR7-CD27-CD28-) also to associate with better survival. These findings suggest that better retention of memory cells specific for previously encountered antigens may provide a survival advantage in this particular population. Given the prevalence of Cytomegalovirus (CMV) and its reported association with immunosenescence, we tested whether memory for this potential pathogen was relevant to survival. We found that individuals mounting an exclusively pro-inflammatory ex vivo response (TNF, IFN-γ, IL-17) to the major CMV target molecules pp65 and IE1 had a significant survival advantage over those also having anti-inflammatory responses (IL-10). These findings suggest that higher levels of naïve T cells may not necessarily be associated with a survival advantage and imply that the nature of immunosurveillance against CMV may be crucial for remaining longevity, at least in the very elderly.

Influenza vaccination is less effective in the elderly compared to the young. Studies that have attempted to identify immune parameters correlating with satisfactory vaccine responses have yielded inconclusive results. Here, we correlate the distribution of different circulating CD4+ and CD8+ T-cell phenotypes with the humoral response to vaccination with Intanza, an intradermal seasonal vaccine, in 54 individuals of different ages. Subjects were stratified according to age (below or over 60) and presence of a latent infection with Cytomegalovirus (CMV). CMV-seropositivity was significantly associated with a lower response rate to the vaccine in people over but not below 60 yr of age. Unlike reported data, late-differentiated (CD45RA+CCR7-CD27-CD28-) CD4+, but not CD8+ T-cells associated with a poorer vaccine response. Thus, latent CMV infection has a deleterious effect on influenza antibody responses in the elderly, which might be mediated through CD4 T-cells lacking CCR7, CD27 and CD28 and re-expressing CD45RA., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naïve CD8+ T-cells and a higher fraction of late-differentiated CD8+ cells, commonly taken as biomarkers of age-associated compromised adaptive immunity ('immunosenescence'), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42-81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of naïve CD8+ T-cells (defined as CD45RA+CCR7+CD27+CD28+) and greater proportions of late-differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and so-called TEMRA (CD45RA+CCR7-CD27-CD28-) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus.

"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., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Age-associated failing systemic immunity, loosely termed 'immunosenescence', is thought to contribute to the increased incidence and severity of infectious disease in old people. It would therefore be of great practical as well as academic interest to accurately identify which of the multitude of alterations to immune parameters thus far reported are causally related to a person's clinically unfavourable health status, in order to identify the mechanisms of immune ageing and intervene to restore appropriate immunity. This is an enormous current challenge, as it requires longitudinal studies in a very long-lived species. Circumstantial evidence and longitudinal studies limited to the very elderly have begun to reveal 'immune signatures' or biomarkers of immune ageing consisting not of a single parameter, but clusters of parameters increasingly recognized as an 'immune risk profile', or IRP. Although hinted at many years ago, a marked impact of usually asymptomatic infection with the persistent beta-herpesvirus Cytomegalovirus (CMV) on markers of immunosenescence is now becoming incontrovertible. The fascinating cohabitation of CMV with the human immune system, which commits a very significant fraction of its entire resources to CMV-immunosurveillance, may suggest an early-life benefit from infection, which becomes deleterious for the majority of the population only in later life or under pathological conditions.

'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review.

Summary: The umbrella term ‘immunosenescence’ is applied to describe age-associated failing systemic immunity and is believed to contribute to the increased incidence and severity of infectious disease in old animals and people. Very limited studies in man have begun to reveal biomarkers of immune ageing (‘immune signatures’) increasingly recognized as an ‘immune risk profile’ (IRP) predicting mortality in the elderly. Even more limited studies in companion animals seem consistent with the idea that most or all other mammals may also show an IRP. It is of practical and scientific interest to more accurately determine the IRP and to devise interventions to modulate immune ageing. In man, cytomegalovirus (CMV) infection has an enormous impact on biomarkers associated with immunosenescence; it is not clear whether the same is true for a persistent viral infection in other animals. A significant fraction of the human immune system is committed to controlling CMV; this commitment increases with age and may itself cause pathology as a result of maintaining higher systemic levels of inflammatory mediators. It will be interesting to test whether similar phenomena occur in relatively long-lived animals, often sharing a human environment, like cats and dogs, and whether interventions to restore appropriate immunity in companion animals might also be applicable to people. [Copyright &y& Elsevier]