Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes

Larbi, Anis; Douziech, Nadine; Dupuis, Gilles; Khalil, Abdelouahed; Pelletier, Hugues; Guérard, Karl-Philippe; Fülöp, Tamás

doi:10.1189/jlb.0703319

Cited by 116 publications

(94 citation statements)

References 62 publications

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“…We have already shown that the activation of Lck, ERK, and Akt in T cells is altered with aging (Fülöp et al 2012;Larbi et al 2004b). We therefore investigated whether the phosphorylation status of these key signaling molecules can be modulated by HDL to explain the functional effects described above.…”

Section: Effect Of Hdl On Tcr-mediated Signalingmentioning

confidence: 92%

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

Larbi

Fortin

Dupuis

et al. 2014

AGE

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Natural aging is accompanied by a dysregulation of the host immune response that has well-known clinical consequences but poorly defined underlying causes. It has previously been reported that advancing age is associated with an increase in membrane cholesterol level in T cells. The aim of this study was to investigate whether high-density lipoprotein (HDL) can modulate the age-related accumulation of membrane cholesterol in T cells and impact on their subsequent responsiveness. Our data reveal that cholesterol metabolism, influx, and efflux are altered in T cells with aging, which may in part explain the increase in membrane cholesterol level observed in T cells in elderly individuals. HDL was unable to promote reverse cholesterol transport in T cells from elderly subjects with the same efficiency as was observed in T cells from young subjects besides unchanged ABCA-1 and SR-BI expressions. HDL exhibited a short-acting co-stimulatory effect by enhancing T cell production of interleukin-2 (IL-2). Moreover, HDL from healthy normolipemic individuals exerted differential effects on T cell proliferation that depended on the age of the HDL donor. Finally, HDL modulated TCR/CD28 activation by inducing sustained signaling through pLck, pERK, and pAkt. These data suggest that HDL has immunomodulatory effects on T cells that are influenced by age.

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Section: Effect Of Hdl On Tcr-mediated Signalingmentioning

confidence: 92%

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

Larbi

Fortin

Dupuis

et al. 2014

AGE

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“…Other receptors/molecules are located in the peripheral SMAC and migrate into the cSMAC to regulate activation (39). Here, only the signaling molecules/pathways that are known to display age-related changes are shown (53). CD4-or CD8-associated Lck recruits and activates Zeta-associated protein of 70 kDa (ZAP-70) and phospholipase C␥-1 (PLC␥-1) on exclusion of CD45.…”

Section: T-cell Function Activation and Signaling At The Cellular Lmentioning

confidence: 99%

“…The last is associated with several molecules including Vav, influencing cytoskeletal rearrangements (22). Together, these changes in expression (E), phosphorylation (P), or recruitment (R) cause differential activation of mitogen-activated protein kinases (MAPK) and translocation of transcription factors including NF-B, NF-AT, and AP-1 into the nucleus (53,54). This is decreased in aged T-cells and directly affects clonal expansion due to decreased IL-2 production.…”

Section: T-cell Function Activation and Signaling At The Cellular Lmentioning

confidence: 99%

“…Moreover, physical activity may enhance immunity through the release of neuroendocrine factors (88). Additionally, exercise may enhance immunity through indirect effects on psychosocial variables such as depression and mood, thereby attenuating the negative influence of these (53,54,75). The signaling events impaired in aged individuals, which interfered with the formation of the immune synapse, are depicted in FIGURE 4.…”

Section: Sleep/physical Activitymentioning

confidence: 99%

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Aging of the Immune System as a Prognostic Factor for Human Longevity

et al. 2008

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“…Others have reported alterations in early signaling events in old mice (73) and in human T lymphocytes from elderly patients (74), furthering the common characteristics between ex vivo culture expansion and immuosenescence. Three major proteins, Lck, LAT, and ERK, were extracted from the model as having primary roles in accurately predicting cellular age.…”

Section: Discussionmentioning

confidence: 82%

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

Rivet

Hill

et al. 2011

Molecular & Cellular Proteomics

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Adoptive T-cell transfer therapy relies upon in vitro expansion of autologous cytotoxic T cells that are capable of tumor recognition. The success of this cell-based therapy depends on the specificity and responsiveness of the T cell clones before transfer. During ex vivo expansion, CD8؉ T cells present signs of replicative senescence and loss of function. The transfer of nonresponsive senescent T cells is a major bottleneck for the success of adoptive T-cell transfer therapy. Quantitative methods for assessing cellular age and responsiveness will facilitate the development of appropriate cell expansion and selection protocols. Although several biomarkers of lymphocyte senescence have been identified, these proteins in isolation are not sufficient to determine the age-dependent responsiveness of T cells. We have developed a multivariate model capable of extracting combinations of markers that are the most informative to predict cellular age. To acquire signaling information with high temporal resolution, we designed a microfluidic chip enabling parallel lysis and fixation of stimulated cell samples on-chip. The acquisition of 25 static biomarkers and 48 dynamic signaling measurements at different days in culture, integrating single-cell and population based information, allowed the multivariate regression model to accurately predict CD8؉ T-cell age. From surface marker expression and early phosphorylation events following T-cell receptor stimulation, the model successfully predicts days in culture and number of population doublings with R 2 ‫؍‬ 0.91 and 0.98, respectively. Furthermore, we found that impairment of early signaling events following T cell receptor stimulation because of long term culture allows prediction of costimulatory molecules CD28 and CD27 expression levels and the number of population divisions in culture from a limited subset of signaling proteins. The multivariate analysis highlights the information content of both averaged biomarker values and heterogeneity metrics for prediction of cellular age within a T cell population.

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Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes

Cited by 116 publications

References 62 publications

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

Aging of the Immune System as a Prognostic Factor for Human Longevity

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

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