The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age

McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
PLoS Pathogens (Impact Factor: 7.56). 12/2012; 8(12):e1003076. DOI: 10.1371/journal.ppat.1003076
Source: PubMed


As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8+ T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8+ T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41-59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses.

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    • "PBMCs were isolated and frozen using a validated common standard operating procedure [20]. PBMCs were thawed and CMV-reactive T-cells were identified by stimulating PBMCs with a pool of overlapping peptides spanning the immunodominant pp65 protein of CMV (PepTivator pp65, Miltenyi Biotec) according to our published protocols [21]. Briefly, thawed PBMCs were cultured overnight at 37°C and stimulated with CMV peptides (2 ug/ml) for 1 hr at 37°C. "
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    ABSTRACT: To describe T-cell and natural killer (NK) cell phenotypes within nursing home elderly. Nursing home elderly were recruited from four nursing homes in Hamilton, Ontario between September 2010 and December 2011. Healthy adults were recruited from McMaster University between September 2011 and December 2011. Nursing home elderly >=65 years were eligible; those on immunosuppressive medications were excluded. Healthy adults >=18-64 years were eligible. CD8+ and CD4+ T-cells% and their subsets, T-regs% and NK cell subset% were compared between the nursing home elderly and healthy adults. 262 nursing home elderly were enrolled; median age 87 years and 81% were female. 16 healthy adults were enrolled; median age 31 and 50% were female. There was no significant difference between CD8+ T-cell% in nursing home and healthy adults (median 17.1 versus 18.0, p = 0.56), however there were fewer naive CD8 + T-cell% (median 0.9 versus 5.2, p < 0.001), more terminally differentiated CD8 + T-cell% (median 7.3 versus 4.1, p = 0.004) and more senescent T-cell% (median 5.3 versus 3.1, p = 0.04) in the nursing home elderly. There were more CD4+ T-cell% in the nursing home elderly compared to healthy adults (median 45.5 versus 37.1, p = 0.001). Nursing home elderly had a higher CD4+/CD8+ ratio than healthy adults (2.6 versus 1.9, p = 0.048), higher T-reg% (median 1.8 versus 0.8, p < 0.001) and increased mature NK cell% (median 12.1 versus 5.4, p = 0.001) compared to healthy adults. Differences in naive CD8+ T-cells, terminally differentiated and senescent CD8+ T-cells, T-regs and NK cell subsets were similar to studies involving community dwelling elderly. In contrast, the CD4+/CD8+ ratio was higher in nursing home elderly.
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    • "It has been shown that CMV-specific CD8+ T cells from elderly donors retain their proliferative and cytotoxic capacity [23] and that T cells responding to CMV are polyfunctional independently of donor age [24]. Moreover, a recent study does not find differences in the response to West Nile virus in a group of middle age and aged individuals with large expansions of CMV-reactive CD8+ T cells, indicating that CMV infection and the subsequent expansion of CMV-specific CD8+ T cells do not limit the ability of the host to respond to novel antigens [25]. "
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    ABSTRACT: Cytomegalovirus (CMV) latent infection has a deleterious effect on the efficacy of influenza vaccination in the elderly, suggesting that CMV restricts immunological diversity impairing the immune system functionality in old age. Polyfunctional T cells produce multiple cytokines and higher amounts than mono-functional T cells. High number of polyfunctional T cells correlates with better prognosis during infection. Thus, the efficiency of T cell response associates with quality (polyfunctionality) rather than with quantity (percentage of T cells). We analyze the effect of CMV infection on CD8+ T cells polyfunctionality -degranulation (CD107a), IFN-gamma and TNF-alpha production-, from young CMV-seropositive and CMV-seronegative individuals and in middle age CMV-seropositive donors, in response to Staphylococcal Enterotoxin B (SEB). Our results show a higher percentage of polyfunctional CD8+ T cells in young CMV-seropositive individuals compared to CMV-seronegative. Also, we find an expansion of CD8+CD57+ T cells in CMV-seropositive individuals, which are more polyfunctional than CD8+CD57- cells. In middle age individuals there is a higher frequency of SEB-responding CD8+ T cells, mainly TNF-alpha or TNF-alpha/IFN-gamma producers, whereas the percentage of polyfunctional cells (IFN-gamma/TNF-alpha/CD107a) is similar to the percentages found in young CMV-seropositive. Therefore, whereas it has been shown that CMV latent infection can be detrimental for immune response in old individuals, our results indicate that CMV-seropositivity is associated to higher levels of polyfunctional CD8+ T cells in young and middle age donors. This increase in polyfunctionality, which can provide an immunological advantage in the response to other pathogens, is due to a CD8+CD57+ T cell expansion in CMV-seropositive individuals and it is independent of age. Conversely, age could contribute to the inflammation found in old individuals by increasing the percentage of cells producing pro-inflammatory cytokines. These findings highlight the necessity of further studies on the benefits/detrimental effects of CMV infection in the response to vaccination and other infections.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Immunosenescence is defined as age-associated changes in the immune response. There is a general misconception that the immune system of the elderly becomes hypo-responsive or broadly non-functional; however, although many aspects of immunity decline, this does not occur uniformly and some elements of the aging immune response are preserved (e.g., CD8+ T cell polyfunctionality) (Lelic et al., 2012) while others are enhanced (e.g., pro-inflammatory cytokine production by macrophages) (Olivieri et al., 2013). Consequently, some researchers suggest that the term immunosenescence should be replaced with the phrase “senescent immune remodeling” to better describe the plasticity of the aging immune system (Dewan et al., 2012). "
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    ABSTRACT: Vaccination remains the most effective prophylactic intervention for infectious disease in the healthcare professional's toolkit. However, the efficacy and effectiveness of vaccines decrease with age. This becomes most apparent after an individual reaches 65-70 years old, and results from complex changes in the immune system that occur during aging. As such, new vaccine formulations and strategies that can accommodate age-related changes in immunity are required to protect this expanding population. Here, we summarize the consequences of immunosenescence on vaccination and how novel vaccination strategies can be designed to accommodate the aging immune system. We conclude that current vaccination protocols are not sufficient to protect our aging population and, in some cases, are an inefficient use of healthcare resources. However, researchers and clinicians are developing novel vaccination strategies that include modifying who and when we vaccinate and capitalize on existing vaccines, in addition to formulating new vaccines specifically tailored to the elderly in order to remedy this deficiency.
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