The deterioration in immune function with aging is thought to make a major contribution to the increased morbidity and mortality from infectious disease in old age. One aspect of immune senescence is the reduction in CD8 T cell repertoire as due to the accumulation of oligoclonal, memory T cells and a reduction in the naive T cell pool. CD8 T cell clonal expansions accumulate with age, but their antigenic specificity remains unknown. In this study, we show that in elderly individuals seropositivity for human CMV leads to the development of oligoclonal populations of CMV-specific CTL that can constitute up to one-quarter of the total CD8 T cell population. Furthermore, CMV-specific CTL have a highly polarized membrane phenotype that is typical of effector memory cells (CD28−, CD57+, CCR7−). TCR analyses show that CMV-specific CTL have highly restricted clonality with greater restriction in the larger expansions. Clonal analysis of the total CD8 T cell repertoire was compared between CMV-seropositive and CMV-seronegative donors. Thirty-three percent more clonal expansions were observed in CMV-seropositive donors in comparison with seronegative individuals. These data implicate CMV as a major factor in driving oligoclonal expansions in old age. Such a dramatic accumulation of virus-specific effector CTL might impair the ability to respond to heterologous infection and may underlie the negative influence of CMV seropositivity on survival in the very elderly.

Aging in humans is associated with increased infections and the reduced proliferative capacity of T cells, part of the more global phenomenon termed immune senescence. The etiology of immune senescence is unknown but the accumulation of virus-specific memory T cells may be a contributory factor. We have examined CD8 T cell responses to two persistent herpesvirus infections, CMV and EBV, and to a recurrent virus infection, influenza, in different age cohorts of healthy donors using HLA-peptide tetramers and intracellular cytokine detection. Of these, CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging.

SummaryAgeing is associated with evidence of immune deficiency and dysregulation. Key changes in the immune system with ageing include a progressive reduction in naive T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells.

SummaryCytomegalovirus (CMV) infects most individuals and elicits a strong CMV-specific immune response. We have studied the influence of CMVseropositivity on the size of lymphoid subsets in healthy donors and demonstrate that the virus substantially modulates the peripheral lymphoid pool. CD8+ T cell numbers are increased in all CMV-seropositive individuals because of a striking 60% increment in the CD8 + T cell memory pool. The CD45RA + resting memory pool is doubled after CMV infection and increases further with age. The magnitude of the naïve CD8 + T cell pool is dramatically reduced in CMV-seropositive individuals at all ages, and this accelerates the physiological decline by approximately 40 years. The number of CD4 + effector memory T cells is increased in CMV-seropositive individuals and is differentially accommodated by a reduction in the number of naïve and central memory CD4+ T cells in young and elderly donors respectively. CMVseropositivity also increases the total number of B cells in older donors and suppresses the number of CD5 + B cells. These data reveal that CMV has a profound influence on the immune system of all healthy individuals and add to growing concern regarding the clinical and immunomodulatory significance of CMV infection in healthy donors.

Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8 ؉ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4 ؉ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4 ؉ T-cell immune response increases from a mean of 2.2% of the CD4 ؉ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4 ؉ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4؉ T-cell repertoire in healthy aged donors, including an increase in CD57؉ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4 ؉ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.Healthy aging is associated with the development of a number of phenotypic and functional abnormalities of the immune system. These include the accumulation of memory T cells, impaired functional responses in vitro, and a reduction in the response rate to vaccinations (5, 8). These findings are associated with the phenomenon of immune senescence and are thought to underlie the increased rate of infectious disease that is seen in elderly individuals (7).The magnitude of the cellular immune response to a number of pathogens has been studied in donors of different ages and has revealed that cellular immunity to viruses such as influenza virus and varicella-zoster virus decreases with advancing age (3). In marked contrast to these findings, the CD8 T-cell response to cytomegalovirus (CMV) increases markedly with age, such that it may represent over 40% of the CD8 ϩ T-cell pool (14,15). A similar observation has been seen with the CD8 T-cell immune response to murine cytomegalovirus (13). There has been speculation that this accumulation of memory CD8 T cells may itself contribute to features of immune senescence, and this idea has gained support from studies of elderly donors in whom CMV seropositivity is associated with the development of an immunological phenotype associated with impaired survival (16,29).CD4 T cells are important in the induction and regulation of the cellular immune response to pathogens, and an impaired CMV-specific CD4 T-cell immune response has been correlated with prolonged viral secretion following neonatal infection (10). Currently little is known with regard to how the magnitude or functional properties of the CD4 T-cell immune response to CMV are influenced by aging. Here we have studied the CMV-specific CD4 T-cell response to CMV viral lysate in a cohort of 30 ...

Replication of human cytomegalovirus is controlled by a vigorous CD8 T cell response. The persistent nature of infection is believed to periodically stimulate T cell responses resulting in considerable expansions of virus-specific CD8 T cells over time. In this study, we describe the magnitude and breadth of CD8 T cell responses against the immunodominant viral Ags, IE-1 and pp65, in acute and long-term infection using the IFN-γ ELISPOT assay. Simultaneously, we have identified several novel MHC class I restricted CD8 T cell epitopes. Acute phase responses in immunocompetent donors appear to be extremely focused as early as 1 week post diagnosis with dominant peptide-specific responses observed against both proteins. These dominant responses remain detectable at all later time points over a 4-year follow-up. Interestingly the IE-1 responses show an increase over time whereas the pp65 responses do not, which contrasts with data showing that responses against both Ags are elevated in elderly individuals. We also observe the rapid emergence of an effector memory phenotype for virus-specific CD8 T cells as observed in persistent infection. Over time the revertant CD45RApos effector cell population is also expanded, and this is more evident in the preferentially expanded IE-1 responses. We postulate that periodic low-level virus reactivation after the acute infection phase preferentially stimulates these responses whereas pp65-specific T cell expansions probably occur during the infrequent episodes of lytic viral replication or secondary infection.

Background: Natural killer (NK) cells are cytotoxic lymphocytes that lack CD3 and express variable levels of CD16, CD56 and CD57. In recent years NK cells have been categorised into two major groups based on the level of CD56 expression. This phenotypic classification correlates with functional activity as CD56 bright NK cells are the major cytokine producing subset whereas CD56 dim NK cells exhibit greater cytotoxic activity. Previous studies have revealed a reduction in total NK cell numbers in association with ageing and this study sought to determine the potential influence of ageing on the number of NK cell subsets within peripheral blood.

The following study investigated wrist torque strength measurements of a group of younger and older adults. The aim of the study was to examine the impact of shape, diameter and height of lid on wrist torque opening strength. Forty participants took part in the study in four groups, younger males and females and older males and females. Data were collected for 12 test pieces. Anthropometric data were also obtained for stature, weight, hand breadth, hand length, chuck grip force, grip force, lateral grip force and pinch grip force. The analysis of the wrist torque strength measurements found that participants could exert greater force with square test pieces compared to circular test pieces of the same diameter. Examination of the circular test pieces found that as diameter and height increased, so did torque exertion data for the test pieces between 20 mm and 50 mm diameter. The surface area of the test pieces was found to be highly correlated with the level of torque exertion, thus a linear model was developed to describe this relationship. The model could be used to predict maximal torque closure levels for use in the packaging industry. The anthropometric data revealed that as height, weight, hand length and hand breadth increased, there was a correlation with the levels of torque exerted. Future research needs to further examine the relationship between surface area and torque exerted and the design of spherical lids to increase the contact area between the hand and the lid.