Laxman Nayak

Cytomegalovirus Seropositivity Drives the CD8 T Cell Repertoire Toward Greater Clonality in Healthy Elderly Individuals

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.

Herpesvirus-Specific CD8 T Cell Immunity in Old Age: Cytomegalovirus Impairs the Response to a Coresident EBV Infection

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.

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

Cytomegalovirus (CMV) infects most individuals and elicits a strong CMV‐specific immune response. We have studied the influence of CMV‐seropositivity 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. CMV‐seropositivity 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.

The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire.

ABSTRACT 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.

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

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.

Ageing is associated with a decline in peripheral blood CD56bright NK cells

BackgroundNatural 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 CD56bright NK cells are the major cytokine producing subset whereas CD56dim 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.ResultsThe number of NK (CD56+CD3-) cells within peripheral blood did not change with increasing age. The number of CD56dim NK cells also remained stable with ageing. In contrast the absolute number of CD56bright NK cells within peripheral blood declined by 48% with ageing from a mean of 15.6/μl in individuals aged 20–40 years to 8.1/μl in those aged 60+ years (p = 0.0004).ConclusionThe number of CD56bright NK cells within peripheral blood declines with age. As this population plays a central role in cytokine secretion during the innate immune response this decline may contribute to impaired immune regulation in elderly individuals

Website design attributes for retrieving health information by older adults: an application of architectural criteria

The objectives of this research were to identify design attributes to develop easy-to-use websites for older adults. Forty-one males and 58 females (age range 58–90) were asked to retrieve information on a health-related topic from the NHS Direct and Medicdirect websites, and were asked to fill in a website evaluation questionnaire. An exploratory factor analysis of data identified navigation/search usability, link usability, usefulness and colour as important dimensions of a senior-friendly website. A two-stage, three-component regression model with these dimensions as predictor variables and the satisfaction level in using a website as the dependent variable has been proposed.

Website task performance by older adults

The present study examined influences of fluid intelligence and website experience on a website task by 99 community-dwelling older adults (41 males, 58 females, age range 58 – 90 years) who were screened for visual acuity and major health problems. They were divided into three groups, dependent on their prior website experience (19 with no prior website experience, 55 with low website experience and 25 with high website experience). Perpendicular to this, the participants were divided into low- and high-fluid intelligence groups and into young – old and old – old age groups. Participants performed a website information retrieval task using three health information websites. Performance was assessed by the time taken to retrieve target information. Overall, the three websites significantly differed in the time taken to locate the target information. The website task performance was not significantly influenced by fluid intelligence score or age, but there was a significant influence by prior website experience.

Intelligence, Belief in the Paranormal, Knowledge of Probability and Aging

ABSTRACT In young adults, preparedness to accept improbable events as planned rather than due to chance is predictive of the level of belief in the paranormal, possibly underpinned by lower intelligence levels (Musch and Ehrenberg, 2002). The present study, using a sample of 73 older participants aged 60–84 years failed to find any relationship between age, intelligence, probability knowledge, and belief in the paranormal. The findings further question the assumptions that studies on knowledge and belief in younger adults can be unquestioningly transposed onto older adults. An explanatory model of the findings is presented.