The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.

In the previous OCTO longitudinal study, we identified an immune risk phenotype (IRP) of high CD8 and low CD4 numbers and poor proliferative response. We also demonstrated that cognitive impairment constitutes a major predictor of nonsurvival. In the present NONA longitudinal study, we simultaneously examine in a model of allostatic load IRP and compromised cognition in 4-year survival in a population-based sample (n = 138, 86-94 years). Immune system measurements consisted of determinations of T-cell subsets, plasma interleukin 6 and cytomegalovirus and Epstein-Barr virus serology. Interleukin 2 responsiveness to concanavalin A, using data from the previous OCTO (octogenarians) immune study, hereafter OCTO immune, was also examined. Cognitive status was rated using a battery of neuropsychological tests. Logistic regression indicated that the IRP and cognitive impairment together predicted 58% of observed deaths. IRP was associated with late differentiated CD8+CD28-CD27- cells (p < .001), decreased interleukin 2 responsiveness (p < .05) and persistent viral infection (p < .01). Cognitive impairment was associated with increased plasma interleukin 6 (p < .001). IRP individuals with cognitive impairment were all deceased at the follow-up, indicating an allostatic overload.

'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.

The human immune system evolved to defend the organism against pathogens, but is clearly less well able to do so in the elderly, resulting in greater morbidity and mortality due to infectious disease in old people, and higher healthcare costs. Many age-associated immune alterations have been reported over the years, of which probably the changes in T cell immunity, often manifested dramatically as large clonal expansions of cells of limited antigen specificity together with a marked shrinkage of the T cell antigen receptor repertoire, are the most notable. It has recently emerged that the common herpesvirus, cytomegalovirus (CMV), which establishes persistent, life-long infection, usually asymptomatically, may well be the driving force behind clonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. In those few who are not CMV-infected, another even more common herpesvirus, the Epstein-Barr virus, appears to have the same effect. These virus-driven changes are less marked in "successfully aged" centenarians, but most marked in people whom longitudinal studies have shown to be at higher risk of death, that is, those possessing an "immune risk profile" (IRP) characterized by an inverted CD4:8 ratio (caused by the accumulation primarily of CD8(+) CD28(-) cells). These findings support the hypothesis that persistent herpesviruses, especially CMV, act as chronic antigenic stressors and play a major causative role in immunosenescence and associated mortality.

Earlier we identified an Immune Risk Profile (IRP) of very old individuals, 86-94 years of age, characterised by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and an increase in the numbers of CD3+CD8+CD28- cells. In the present study we included data from a population-based sample in the age range of 20-79 years to examine the prevalence of individuals with an inverted CD4/CD8 ratio relative to age and gender across the entire adult lifespan. Immunological monitoring that was conducted included analysis of the numbers of T-cells in the subsets CD3+, CD3+CD4+, and CD3+CD8+ as well as CD3+CD8+CD28+, CD3+CD8+CD28-, and CD8+CD45RA+CCR7+. There was found to be a significant lowering of the numbers of CD3+, CD3+CD4+, and CD3+CD8+, and of the CD8+CD45RA+CCR7+ cells across the adult life-span. Notably, the prevalence of individuals with an inverted CD4/CD8 ratio increased from about 8% in the age range of 20-59 years to about 16% in the age range of 60-94 years. The mortality rate in individuals with an inverted CD4/CD8 ratio also increased significantly above the age of 60. Interestingly, the proportion of individuals with an inverted CD4/CD8 ratio was found to be significantly higher in men, whereas the numbers of CD3+CD4+ helper and CD8+CD45RA+CCR7+ naïve cells and the CD4/CD8 ratio were found to be significantly higher in women. These results highlight the importance of functioning of the thymus in the development of IRP and may partly account for the differences between sexes in terms of longevity.

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The Swedish OCTO and NONA immune longitudinal studies were able to identify and confirm an immune risk profile (IRP) predictive of an increased 2-year mortality in very old individuals, 86–94 years of age. The IRP, was associated with persistent cytomegalovirus infection and characterized by inverted CD4/CD8 ratio and related to expansion of terminally differentiated effector memory T cells (TEMRA phenotype). In the present HEXA immune longitudinal study, we have examined a younger group of elderly individuals (n = 424, 66 years of age) in a population-based sample in the community of Jönköping, Sweden, to examine the relevance of findings previously demonstrated in the very old. Immunological monitoring that was conducted included T cell subsets and CMV-IgG and CMV-IgM serology. The result showed a prevalence of 15 % of individuals with an inverted CD4/CD8 ratio, which was associated with seropositivity to cytomegalovirus and increases in the level of TEMRA cells. The proportion of individuals with an inverted CD4/CD8 ratio was significantly higher in men whereas the numbers of CD3+CD4+ cells were significantly higher in women. In conclusion, these findings are very similar to those previously found by us in the Swedish longitudinal studies, suggesting that an immune profile previously identified in the very old also exists in the present sample of hexagenerians. Therefore, it will be important to examine clinical parameters, including morbidity and mortality, to assess whether the immune profile also is a risk profile associated with higher mortality in this sample of hexagenerians.