Age-Related Decline of Perforin Expression in Human Cytotoxic T Lymphocytes and Natural Killer Cells

Rukavina, Daniel; Laškarin, Gordana; Rubeša, Gordana; Štrbo, Nataša; Bedenicki, Ivica; Manestar, Darko; Glavas, Mario; Christmas, Stephen E.; Podack, Eckhard R.

doi:10.1182/blood.v92.7.2410

Cited by 119 publications

(41 citation statements)

References 42 publications

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“…Similar data for perforin expression were reported previously (Mariani et al. , 1996), although one group has reported reduced perforin expression with aging (Rukavina et al. , 1998).…”

Section: Discussionsupporting

confidence: 89%

Reduced release and binding of perforin at the immunological synapse underlies the age‐related decline in natural killer cell cytotoxicity

Hazeldine¹,

Hampson²,

Lord³

2012

Aging Cell

143

120

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SummaryPhysiological aging is accompanied by a marked reduction in natural killer (NK) cell cytotoxicity (NKCC) at the single cell level, but the underlying mechanisms are unknown. To address this issue, we isolated NK cells from healthy young (£ 35 years) and old (£ 60 years) subjects and examined the effect of age on events fundamental to the process of NKCC. Simultaneous assessment of NKCC and NK cell-target cell conjugate formation revealed a marked age-associated decline in NK cell killing but comparable conjugate formation, indicating a post-target cell binding defect was responsible for impaired NKCC. Despite a reduction in the proportion of NK cells expressing the activatory receptor NKp46, NK cells from old donors were not hyporesponsive to stimulation, as no age-associated difference was observed in the expression of the early activation marker CD69 following target cell coculture. Furthermore, intracellular levels of the key cytotoxic effector molecules perforin and granzyme B, and the fusion of secretory lysosomes with the NK cell membrane were also similar between the two groups. However, when we examined the binding of the pore-forming protein perforin to the surface of its target cell, an event that correlated strongly with target cell lysis, we found the percentage of perforin positive target cells was lower following coculture with NK cells from old subjects. Underlying this reduction in binding was an age-associated impairment in perforin secretion, which was associated with defective polarization of lytic granules towards the immunological synapse. We propose that reduced perforin secretion underlies the reduction in NKCC that accompanies physiological aging.

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“…Similar data for perforin expression were reported previously (Mariani et al. , 1996), although one group has reported reduced perforin expression with aging (Rukavina et al. , 1998).…”

Section: Discussionsupporting

confidence: 89%

Reduced release and binding of perforin at the immunological synapse underlies the age‐related decline in natural killer cell cytotoxicity

Hazeldine¹,

Hampson²,

Lord³

2012

Aging Cell

143

120

View full text Add to dashboard Cite

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“…Patients infected with HIV or hepatitis B virus (HBV) typically show a massive decrease in lymphocyte glutathione levels and a massive loss of natural killer (NK) cell activity and other immune functions (Eck et al 1989;Ullum et al 1995;Watanabe et al 2000;Azzoni et al 2002). It has also been shown that the absolute number of NK cells and the NK cell activity per cell decreases with age (Rukavina et al 1998). NK cells play an important role in the protection against viral or bacterial infections (Bukowski et al 1985;Rager-Zisman et al 1987;Scalzo 2002;Vankayalapati et al 2004;Warfield et al 2004), and in the suppression of tumours (Kim et al 2000;Tahir et al 2001).…”

Section: (G) Immune Functionsmentioning

confidence: 99%

Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?

Dröge

2005

Phil. Trans. R. Soc. B

189

124

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Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.

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“…Most studies have reported increased percentages of NK cells within blood mononuclear cells (BMNC) 32 , 33 , 34 and increased or unaltered concentrations in the blood 32 , 34 . Furthermore, there is a general consensus that NK cells from elderly humans show decreased cytotoxic capacity on a ‘per cell’ basis 35 , 36 . It has been suggested that increased concentrations of NK cells in the blood compensate for the decreased cytotoxicity per NK cell 7 .…”

Section: Ageing and Immune Functionmentioning

confidence: 99%

Effects of exercise on the immune system in the elderly population

Bruunsgaard

Pedersen

2000

Immunol Cell Biol

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Immunosenescence is characterized by impaired cellular immune function concomitant with increased inflammatory activity. Immune dysfunction is associated with increased mortality risk in elderly people. An important part of human ageing is characterized by a decline in the ability of individuals to adapt to environmental stress. Exercise has been suggested as a prototype for studying the effects of stress factors on the cellular immune system. Studies of interactions between an acute bout of exercise and immune function may be a useful and an ethically acceptable tool to investigate cell trafficking, immune mobilization/deficiency and the acute phase response during physical stress situations in relation to human ageing. Elderly humans have a preserved ability to recruit T lymphocytes and NK cells in response to an acute bout of exercise. Physical exercise training programs do not result in major restoration of the senescent immune system in humans. However, highly conditioned elderly humans seem to have a relatively better preserved immune system, although it is not possible to conclude if this is linked to training or other lifestyle-related factors.

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Age-Related Decline of Perforin Expression in Human Cytotoxic T Lymphocytes and Natural Killer Cells

Cited by 119 publications

References 42 publications

Reduced release and binding of perforin at the immunological synapse underlies the age‐related decline in natural killer cell cytotoxicity

Reduced release and binding of perforin at the immunological synapse underlies the age‐related decline in natural killer cell cytotoxicity

Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?

Effects of exercise on the immune system in the elderly population

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