Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)

Ouyang, Qing; Wagner, Wolfgang; Voehringer, David; Wikby, Anders; Klatt, Tatjana; Walter, Steffen; Müller, Claudia; Pircher, Hanspeter; Pawelec, Graham

doi:10.1016/s0531-5565(03)00134-7

Cited by 208 publications

(158 citation statements)

References 35 publications

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“…The expression of KLRG1 rises dramatically with age, with greater than 90% expression of KLRG1 being seen on CD8 + T cells in individuals over 65 years of age (Ouyang et al 2003;Ito et al 2006;Henson et al 2009). The expression of KLRG1 increases not only with age but also with differentiation, with the highest percentage of expression being seen on memory cells and highly differentiated end stage cells (Voehringer et al 2002;Thimme et al 2005).…”

Section: Klrg1-more Than a Marker For T Cell Memorymentioning

confidence: 99%

KLRG1—more than a marker for T cell senescence

Henson

Akbar

2009

AGE

152

125

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The co-inhibitory receptor killer-cell lectin like receptor G1 (KLRG1) is expressed on NK cells and antigen-experienced T cells and has been postulated to be a marker of senescence. Whilst KLRG1 has frequently been used as a marker of cellular differentiation, data are emerging indicating that KLRG1 plays an inhibitory role. In this review we examine evidence highlighting this view of KLRG1 with emphasis on the functional defects that arise during T cell differentiation with age that may, in part, be actively maintained by inhibitory receptor signalling.

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Section: Klrg1-more Than a Marker For T Cell Memorymentioning

confidence: 99%

KLRG1—more than a marker for T cell senescence

Henson

Akbar

2009

AGE

152

125

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“…FOXP3, an antigen previously associated with regulatory CD4 T cells, has now been shown to be present on CD8 + CD28 − T cells from cancer patients [29]. The inhibitory killer cell lectin-like receptor G1 (KLRG1) is expressed on clonal populations of CD8 T cells that are non-proliferative, linking this marker with the senescent phenotype as well [30]. Other cell surface marker changes, including loss of CD27 expression, may also be informative in defining the true end stage CD8 memory cell.…”

Section: Senescent Cd8 T Cells Accumulate In Vivomentioning

confidence: 99%

Telomerase induction in T cells: A cure for aging and disease?

Effros

2007

Experimental Gerontology

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Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 co-stimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8 + CD28 − T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically-suitable formulation.

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“…Phenotypical changes in the immune system attributable to CMV are most visible in the T‐cell compartment, coinciding with clonal expansion and preferential expansion of CD8 + CD45 RA+ CD27 − cytolytic T cells (Khan et al ., 2002; Kuijpers et al ., 2003). CD8 T‐cell responses in CMV‐seropositive elderly are characterized by an accumulation of dysfunctional T cells with short telomeres and low proliferation potential, often considered as replicative senescent (Ouyang et al ., 2003; Griffiths et al ., 2013). Clinically, CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies (Ridker et al ., 1998; Muhlestein et al ., 2000; Sorlie et al ., 2000; Blankenberg et al ., 2001; Simanek et al ., 2009).…”

Section: Introductionmentioning

confidence: 99%

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

et al. 2015

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SummaryAlthough chronic infection with cytomegalovirus (CMV) is known to drive T lymphocytes toward a senescent phenotype, it remains controversial whether and how CMV can cause coronary heart disease (CHD). To explore whether CMV seropositivity or T‐cell populations associated with immunosenescence were informative for adverse cardiovascular outcome in the very old, we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65‐month follow‐up (47.3% survival rate). CMV‐seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%, P = 0.030) compared to CMV‐seronegative participants together with lower CD4/CD8 ratio (1.7 vs. 4.1, P < 0.0001) and higher frequencies of senescence‐like CD4 memory cells (41.1% vs. 4.5%, P < 0.001) and senescence‐like CD8 memory cells (TEMRA, 28.1% vs. 6.7%, P < 0.001). CMV seropositivity was also associated with increased six‐year cardiovascular mortality (HR 1.75 [1.09–2.82], P = 0.021) or death from myocardial infarction and stroke (HR 1.89 [107–3.36], P = 0.029). Gender‐adjusted multivariate Cox regression analysis revealed that low percentages of senescence‐like CD4 T cells (HR 0.48 [0.32–0.72], P < 0.001) and near‐senescent (CD27 negative) CD8 T cells (HR 0.60 [0.41–0.88], P = 0.029) reduced the risk of cardiovascular death. For senescence‐like CD4, but not near‐senescent CD8 T cells, these associations remained robust after additional adjustment for CMV status, comorbidities, and inflammation markers. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T‐cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.

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Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)

Cited by 208 publications

References 35 publications

KLRG1—more than a marker for T cell senescence

KLRG1—more than a marker for T cell senescence

Telomerase induction in T cells: A cure for aging and disease?

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

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