Anders Wikby

Cytomegalovirus infection: A driving force in human T cell immunosenescence

Abstract:u2002 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.

The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20–100 years of age

Earlier we identified an Immune Risk Profile (IRP) of very old individuals, 86–94xa0years 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 20–79xa0years 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 20–59xa0years to about 16% in the age range of 60–94xa0years. 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.

Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ″immune risk phenotype” (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

Dysregulation of T-cell function in the elderly : scientific basis and clinical implications.

The function of the immune system is to maintain body integrity by defending against infections, cancers, autoimmune diseases and inflammation-related chronic diseases. The immune response is known to become defective with aging, leading to decreased longevity and appearance of age-related disease. The most important changes occur in T-cell immunity, and are manifested particularly as altered clonal expansion of cells of limited antigen specificity. The causes of these alterations are multifactorial, and include thymic involution, T-cell subset changes and signal transduction alterations. The clinical consequences of these changes are not well defined, except for their extremely important negative impact on defence against infections, especially by new pathogens, and decreased responses to vaccination. Considering the public health consequences of decreased immune competence in old age, strategies for immune response modulation are desirable to decrease the health burden for the elderly and improve their quality of life.

The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study

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, 86–94xa0years 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 (nu2009=u2009424, 66xa0years 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 15xa0% 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.

Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity

Cytomegalovirus (CMV) infection induces profound changes in different subsets of the cellular immune system. We have previously identified an immune risk profile (IRP) where CMV-associated changes in the T cell compartment, defined as a CD4/CD8 ratiou2009<u20091, are associated with increased mortality in elderly people. Since natural killer (NK) cells have an important role in the defense against viral infections, we examined whether the expansion of CD8u2009+u2009T cells seen in individuals with CD4/CD8 ratiou2009<u20091 is coupled to a parallel skewing of the NK cell compartment. A number of 151 subjects were examined with CMV serology and a flow cytometry panel for assessment of T cell and NK cell subsets. CMV-seropositive individuals had higher frequencies of CD57u2009+u2009and NKG2C + NK cells and lower frequencies of NKG2A + NK cells, in line with a more differentiated NK cell compartment. Intriguingly, however, there was no correlation between CD4/CD8 ratio and NK cell repertoires among CMV-seropositive donors, despite the profound skewing of the T cell compartment in the group with CD4/CD8 ratio < 1. Conversely, donors with profound expansion of NK cells, defined as NKG2C + NK cells with high expression of CD57 and ILT-2, did not display more common changes in their T cell repertoire, suggesting that NK cell expansion is independent of the T cell-defined IRP. Altogether, these results indicate that the effect of CMV on CD8 T cells and NK cells is largely nonoverlapping and independent.

The Immune Risk Profile and Associated Parameters in Late Life: Lessons from the OCTO and NONA Longitudinal Studies

The OCTO Immune Longitudinal Study is a population-based study of ageing in a sample of 102 Swedish octogenarians with the aim to explore age changes of the immune system using a sample selected for good health. Data collection was performed in 1989, 1990, 1991 and 1997. An Immune Risk Profile (IRP) associated with increased mortality was characterized by high CD8+, low CD4+ T-cell counts and a poor T-cell proliferative response, inversion of the CD4/CD8 ratio and evidence of persistent cytomegalovirus infection was identified. The subsequent NONA Immune Longitudinal Study of 138 Swedish nonagenarians was performed in 1999, 2001, 2003, and 2005, not excluding individuals due to compromised health. The overall aim was to examine predictive factors for longevity and to further investigate in greater depth the immune risk profile identified in the OCTO Immune Study in the context of functional and disability parameters also examined in the NONA. The immune panel included the analysis of T-cell subsets, inflammatory markers, virus serology, cytokines, TCR clonotype mapping, and functional and phenotypic analysis of virus specific CD8+ cells by HLA/peptide multimers, in collaborations between participants of the EU funded T-CIA project.

Perforin, CD28 and CD95 expression in circulating CD4 and CD8 cells as predictors of head and neck (H&N) cancer patient survival

AbstractLong-term survival of H&N cancer patients has not improved significantly over the last 30xa0years. The possibility of using circulating blood cell phenotypes as a prognostic biomarker of H&N cancer patient was investigated in this study. Pre-treatment, circulating T lymphocyte subpopulations as well as the survival time of the patients in question were studied. Upregulated CD4+ perforin+ and CD8+ CD95+ but downregulated CD4+ CD28+ (pxa0<xa00.001) were detected in H&N cancer patients. With 3xa0years of follow-up time, an increase in the frequency of the pre-treatment, circulating CD4+ perforin+ cells and CD8+ perforin+ cells was showed to have reverse effects on the survival time in H&N cancer patients (pxa0<xa00.01). Detection of perforin+ frequency in CD4+ and CD8+ lymphocyte by FACS is fast, simple and cost-effective. A potential role of perforin expression in CD4+ and CD8+ cells as a prognostic biomarker for H&N cancer patient in the clinical setting was suggested.n

Immune Risk Phenotypes and Associated Parameters in Very Old Humans: A Review of Findings in the Swedish NONA Immune Longitudinal Study

In the previous OCTO immune longitudinal study of free-living subjects >85 yr. selected for good health, we identified an Immune Risk Phenotype (IRP) associated with increased mortality. The IRP was characterised by high CD8+, low CD4+ T-cell counts and a poor T-cell proliferative response, inversion of the CD4/CD8 ratio and evidence of persistent cytomegalovirus infection. In the NONA immune longitudinal study the aim was to examine whether the same IRP parameters applied to a population-based sample aged 86–94 years who were not selected for very good health. More sophisticated analytical parameters were studied, as well as the role of inflammatory processes in relation to longevity. The immune panel included the analysis of T-cell subsets inflammatory markers, virus serology, cytokines, TCR clonotype mapping and functional and phenotypic analysis of virus-specific CD8+ cells by HLA/peptide multimers, in collaborations between participants of the EU funded T-CIA project.

CD4/CD8 ratio < 1 is associated with lymphocyte subsets, CMV and gender in 71-year old individuals: 5-Year follow-up of the Swedish HEXA Immune Longitudinal Study

HighlightsCD4/CD8 ratio < 1, CMV IgG+ status and T cell repertoire and response are associated.Changes over 5 years for CD3+, CD4+, CD8+, CD19+ and CD4/CD8 ratio are found.The proportion of individuals with CD4/CD8 ratio < 1 increases over 5 years.The proportion of individuals with CD4/CD8 ratio < 1 was higher in men than in women.There was no significant association between CD4/CD8 ratio < 1 and 5‐year mortality.