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Ouyang, Qing; Wagner, Wolfgang; Wikby, Anders; Walter, Steffen; Aubert, Geraldine; Dodi, Anthony I.; Travers, Paul; Pawelec, Graham

doi:10.1023/a:1024580531705

Cited by 218 publications

(56 citation statements)

References 45 publications

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“…In agreement with this, our detailed subset analysis indicated that several subsets with just 1 or 2 of the measured functions were increased (eg, CD8 + T cells displaying IFN-γ alone or IFN-γ and degranulation). Studies conducted over a decade ago suggested that, in very old people, the expansion of UL83-specific T cells (recognizing specific epitopes in a narrow HLA context) was linked to functional exhaustion [22, 23]. The individuals examined in that work were similar in age to our oldest old group, and the decrease in polyfunctionality we have measured in this group might be a correlate of the functional exhaustion reported in these earlier studies, which used fewer activation markers.…”

Section: Discussionmentioning

confidence: 99%

Functional Diversity of Cytomegalovirus–Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size

Bajwa¹,

Vita

Vescovini

et al. 2016

J Infect Dis.

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Background. Parallel upregulation of several T-cell effector functions (ie, polyfunctionality) is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of cytomegalovirus (CMV)–specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages.Methods. Polychromatic flow cytometry was used to analyze the functional diversity (ie, CD107, CD154, interleukin 2, tumor necrosis factor, and interferon γ expression) of CD4+ and CD8+ T-cell responses to 19 CMV proteins in a large group of young and older United Kingdom participants. A group of oldest old people (age >85 years) was included to explore these parameters in exceptional survivors. Polyfunctionality was assessed for each protein-specific response subset, by subset and in aggregate, across all proteins by using the novel polyfunctionality index.Results. Polyfunctionality was not reduced in healthy older people as compared to young people. However, it was significantly related to target protein specificity. For each protein, it increased with response size. In the oldest old group, overall T-cell polyfunctionality was significantly lower.Discussion. Our results give a new perspective on T-cell polyfunctionality and raise the question of whether maintaining polyfunctionality of CMV-specific T cells at older ages is necessarily beneficial.

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Section: Discussionmentioning

confidence: 99%

Functional Diversity of Cytomegalovirus–Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size

Bajwa¹,

Vita

Vescovini

et al. 2016

J Infect Dis.

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“…It remains to be determined whether MI associated with other persistent infections, such as CMV, also has no effect on the function of memory CD8 T cells with age. In that regard, disparate results were reported in mice(23) and in some of the human studies (39). Another related interesting and unanswered question is whether persistent latent infections and the associate periodic stimulation of memory CD8 T cells have a different effect on the function of aged memory CD8 T cells in longer-lived species, such as non-human primates or humans.…”

Section: Discussionmentioning

confidence: 99%

Functional CD8 T Cell Memory Responding to Persistent Latent Infection Is Maintained for Life

Lang

Nikolich‐Žugich

2011

The Journal of Immunology

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Aging is associated with depressed naïve T-cell responses, but it is less clear whether T-cell memory established early in life also becomes impaired with age. This is particularly important for T-cells responding to latent persistent infection, which need to remain functional and capable of controlling the infection over the lifetime, yet repeated stimulation over the lifetime may dysregulate their maintenance or function, potentially contributing to impaired immunity in the elderly. Systemic infection with HSV-1, a persistent latent virus, is associated with memory inflation (MI) of virus-specific CD8 T-cells. We tested how these inflated memory cells are maintained from adulthood into old age. We found no significant differences in the numbers (blood, spleen), ex-vivo antigen-specific IFNγ production, and in-vivo recall response to HSV-1 (proliferation, IFNγ production, cytolysis) between adult and old memory T-cells. There was a discrete shift from dominantly effector memory (EM) phenotype in the adults to a central memory (CM)-like phenotype in the old mice, with fewer old cells expressing the killer cell lectin-like receptor G1 (KLRG1). Adult and old KLRG1+ memory CD8 T-cells were functionally identical: both produced IFNγ but could minimally proliferate in response to viral challenge. Interestingly, regardless of age, KLRG1+ cells retained the ability to proliferate and survive in response to homeostatic signals, both in vitro (culture with IL-7 and IL-15) and in vivo (expansion following transfer into lymphopenic recipients). This demonstrates that functional effector memory T-cells, including those expressing KLRG-1, are maintained and are functional for life, despite presence of persistent viral infection.

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“…Steadily expanding CD8+ T-cells specific for a few HCMV epitopes dominating the memory CD8+ T-cell population is a hallmark of CMV infection and not observed for other viruses [21]. In the elderly HCMV-specific CD8+ T-cells may cover more than 20% of circulating CD8+ cells [22], a phenomenon called “memory inflation.” In addition, a higher frequency of HCMV specific CD4+ T-cells can be observed in HCMV positive persons. These cells exhibit a CD4+/CD28− phenotype and are classified as terminally differentiated effector memory cells [23].…”

Section: Hcmv Pathogenesis and Modulation Of The Immune System By mentioning

confidence: 99%

Human Cytomegalovirus and Autoimmune Disease

Halenius

Hengel

2014

BioMed Research International

118

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Human cytomegalovirus (HCMV) represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.

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Untitled

Cited by 218 publications

References 45 publications

Functional Diversity of Cytomegalovirus–Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size

Functional Diversity of Cytomegalovirus–Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size

Functional CD8 T Cell Memory Responding to Persistent Latent Infection Is Maintained for Life

Human Cytomegalovirus and Autoimmune Disease

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