Telomere Erosion in Memory T Cells Induced by Telomerase Inhibition at the Site of Antigenic Challenge In Vivo

Reed, John R.; Vukmanovic‐Stejic, Milica; Fletcher, Jean M.; Soares, Maria Augusta; Cook, Jeremy E.; Orteu, Catherine H.; Jackson, Sarah E.; Birch, Katie E.; Foster, Graham R.; Salmon, Mike; Beverley, Peter C. L.; Rustin, M.H.A.; Akbar, Arne N.

doi:10.1084/jem.20040178

Cited by 103 publications

(136 citation statements)

References 44 publications

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“…Cells have developed adapting mechanisms to control excessive stimulation at many levels, from TCR down-regulation and degradation to down-modulation of various signaling molecules (59 -63), and expression of inhibitory receptors like CTLA-4 and lymphocyte activation gene-3 (64 -66). Therefore, by transient dissociation from APC, cells might escape both activation-induced cell death and cell senescence as the consequences of vigorous division (67,68).…”

Section: Discussionmentioning

confidence: 99%

T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation

Munitić

Ryan

Ashwell

2005

The Journal of Immunology

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The commitment of naive T cells to proliferate is a function of the strength and duration of stimuli mediated by the TCR and coreceptors. Ranges of 2–20 h of stimulation have been reported as necessary in vitro. Whether T cells actually experience uninterrupted stimulation for such long periods under physiological conditions is controversial. Here we ask whether commitment to proliferate requires continuous stimulation, or can T cells integrate intermittent periods of stimulation. T cells were stimulated for two short-term (subthreshold) periods (5–7 h) either sequentially or separated by an interval of rest. Naive lymph node T cells were able to integrate interrupted stimulation, even when the duration of rest was as long as 2 days. Furthermore, when short-term-stimulated T cells were separated by density, three populations were observed: low density blasts, intermediate density G1 cells, and high density G0 cells. Low density cells progressed to division without further stimulation, whereas G0 and G1 cells remained undivided. However, after a period of rest, a second subthreshold stimulation caused the G1 but not the G0 fraction to quickly proceed through the cell cycle. We conclude that noncycling T cells in the G1 phase of the cell cycle remain in a state of readiness for prolonged periods of time, and may represent a population of memory-like effectors capable of responding rapidly to antigenic challenge.

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Section: Discussionmentioning

confidence: 99%

T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation

Munitić

Ryan

Ashwell

2005

The Journal of Immunology

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“…In some experiments, absolute numbers of CD8 ϩ subsets were enumerated using Tru-count tubes (BD Biosciences) and Ki67 analysis. PCR was performed with samples adjusted to 500 Ki67 ϩ T cells per reaction (24).…”

Section: Measurement Of Telomerase Activitymentioning

confidence: 99%

The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation

Plunkett

Franzese

Finney³

et al. 2007

The Journal of Immunology

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190

216

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The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8+ T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8+CD28− T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (ζ) chain into primary human CD8+ T cells. Although CD3 ζ-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8+CD28− T cells could up-regulate this enzyme. The further fractionation of CD8+CD28− T cells into CD8+CD28− CD27+ and CD8+CD28−CD27− subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8+CD28−CD27− T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser473 but not the Thr308 phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8+CD28−CD27− T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8+ T cells to be maintained by continuous proliferation in vivo.

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“…Ageing is also associated with impairment of lymphocyte telomerase upregulation and progressive telomere attrition (van de Berg et al 2010), the significance of which being a strong correlation between shortened lymphocyte telomeres and a variety of age-associated pathologies (reviewed in Calado and Young 2009) and predictive of earlier mortality (Cawthon et al 2003). TNFα and IFNα are also implicated in this age-related telomere shortening, as they inhibit lymphocyte telomerase activity (Reed et al 2004;Parish et al 2009). When telomeres reach a critically short length, they initiate a DNA damage response that can induce apoptosis or growth arrest termed replicative senescence, an increasingly recognised important factor in T-cell immunosenescence (reviewed in Akbar and Henson 2011).…”

Section: Cd8mentioning

confidence: 99%

The role of the T cell in age-related inflammation

Macaulay

Akbar

Henson

2012

AGE

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105

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Ageing is accompanied by alterations to T-cell immunity and also by a low-grade chronic inflammatory state termed inflammaging. The significance of these phenomena is highlighted by their being predictors of earlier mortality. We have recently published that the proinflammatory cytokine TNFα is a strong inducer of CD4 + T-cell senescence and T-cell differentiation, adding to the growing body of literature implicating proinflammatory molecules in mediating these critical age-related T-cell alterations. Moreover, the inflammatory process is also being increasingly implicated in the pathogenesis of many common and severe age-related diseases, including cancer, cardiovascular diseases and type 2 diabetes. Furthermore, major age-related risk factors for poor health, such as obesity, stress and smoking, are also associated with an upregulation in systemic inflammatory markers. We propose the idea that the ensuing inflammatory response to influenza infection propagates cardiovascular diseases and constitutes a major cause of influenzarelated mortality. While inflammation is not a negative phenomenon per se, this age-related dysregulation of inflammatory responses may play crucial roles driving age-related pathologies, T-cell immunosenescence and CMV reactivation, thereby underpinning key features of the ageing process.

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Telomere Erosion in Memory T Cells Induced by Telomerase Inhibition at the Site of Antigenic Challenge In Vivo

Cited by 103 publications

References 44 publications

T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation

T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation

The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation

The role of the T cell in age-related inflammation

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