Age-Related Decreases in IL-2 Production by Human T Cells Are Associated with Impaired Activation of Nuclear Transcriptional Factors AP-1 and NF-AT

Whisler, Ronald L.; Beiqing, Liu; Chen, Ming

doi:10.1006/cimm.1996.0109

Cited by 109 publications

(58 citation statements)

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“…These data indicate that impaired expression of the activation marker CD69 in aging by engagement and even by bypassing the TCR. However, reduced activation of lymphocytes from elderly humans seems, therefore, not only to be due to lower expression of CD3 and/or followed by reduced signal transduction (Fulop et al, 1995) after TCR ligation, but also age-related diminished transcription might be involved in our findings (Whisler et al, 1996).…”

Section: Discussionmentioning

confidence: 66%

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

Schindowski

Fröhlich

Maurer

et al. 2002

Mechanisms of Ageing and Development

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The relevance of physiological immune aging is of great interest with respect to determining disorders with pathologic immune function in aging individuals. In recent years, the relevance of changes in peripheral lymphocytes in age-associated neurologic diseases has become more evident. Due to the lack of immunological studies. covering moce than one event after mitogenic activation, we envisaged a new concept in the present study, aiming to investigate several events, starting from T cell receptor (TCR) ligation up to T cell proliferation. In addition, we addressed the question whether changes are present in the subsets (CD4, CDR) with aging. Phosphorylation of tyrosine residues declines with increasing age in CD4+ cells. Fewer levels of CD69 positive cells after 4 h mitogenic activation, altered expression of cytokines (IL2, IFN-7 and TNF-a; 22 h) and lower proliferation (72 h) were detemined in aging. Moreover, it could be shown that CD8" lymphocytes react more effectively to mitogenic stirnulation with referenoe to CD69 expression and proliferation in both age groups ( < 35 and > 60 years old). These data indicate that T cell activation, rnediated by TCR engagement, is significantly impaired in aging and both subsets are affected. However, bypassing the TCR does not fully restore T cell function, indicating that there are more mechanisms involved than impaired signal transduction thwugh TCR only. The results will be discussed in relation to iiheir relevance in neurodegenerative and psychiatric disorders.

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Section: Discussionmentioning

confidence: 66%

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

Schindowski

Fröhlich

Maurer

et al. 2002

Mechanisms of Ageing and Development

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“…Several laboratories have shown that T cells from healthy old humans and mice exhibit a multitude of defects at early stages of the T cell signaling pathways, including changes in serine/threonine and tyrosine phosphorylation (17)(18)(19)(20)(21)(22)(23), development of calcium signals (24), activation of the Raf-1/mitogen-activated protein/extracellular signal-related kinase kinase/ extracellular signal-related kinase (19) and c-Jun N-terminal kinase (JNK) pathways (25)(26) and translocation of cytoplasmic NF-AT (NF-ATc) to the nucleus (27). Most of these alterations are demonstrable within the first 15 min of TCR engagement, and it is not yet clear which of the defects are primary, and which are merely secondary consequences of earlier abnormalities.…”

Section: Single-cell Analyses Reveal Two Defects Inmentioning

confidence: 99%

“…Old impaired activation of transcriptional factors such as NF-ATc (27,28). To see whether defects in the assembly of protein complexes at the site of TCR/APC interaction might contribute to age-dependent alterations in these downstream events, we performed a series of experiments examining both NF-ATc translocation and relocalization of LAT, PLC␥, or c-Cbl in individual T cells.…”

Section: Youngmentioning

confidence: 99%

Single-Cell Analyses Reveal Two Defects in Peptide-Specific Activation of Naive T Cells from Aged Mice

Garcia

Miller

2001

The Journal of Immunology

114

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Confocal fluorescent microscopy was used to study redistribution of membrane-associated proteins in naive T cells from young and old mice from a transgenic stock whose T cells express a TCR specific for a peptide derived from pigeon cytochrome C. About 50% of the T cells from young mice that formed conjugates with peptide-pulsed APC were found to form complexes, at the site of binding to the APC, containing CD3ε, linker for activation of T cells (LAT), and Zap-70 in a central area and c-Cbl, p95vav, Grb-2, PLCγ, Fyn, and Lck distributed more uniformly across the interface area. Two-color staining showed that those cells that were able to relocalize c-Cbl, LAT, CD3ε, or PLCγ typically relocalized all four of these components of the activation complex. About 75% of conjugates that rearranged LAT, c-Cbl, or PLCγ also exhibited cytoplasmic NF-AT migration to the T cell nucleus. Aging had two effects. First, it led to a diminution of ∼2-fold in the proportion of T cell/APC conjugates that could relocalize any of the nine tested proteins to the immune synapse. Second, aging diminished by ∼2-fold the frequency of cytoplasmic NF-AT migration among cells that could generate immune synapses containing LAT, c-Cbl, or PLCγ. Thus naive CD4 T cells from old mice exhibit at least two separable defects in the earliest stages of activation induced by peptide/MHC complexes.

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“…Effects on downstream signaling events have also been reported. Age-related changes have been observed in the initiation of calcium influxes (20,21), the activation of MAPK pathways (including the ERK and JNK pathways) (22)(23)(24)(25), and the synthesis, translocation, and activation of the transcription factors NF-AT (26), AP-1 (25,27), and NF-B (28,29). Most recently, reports have indicated that immune synapse formation is impaired in aged T cells (30,31).…”

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confidence: 99%

Age-Associated Decline in Effective Immune Synapse Formation of CD4+ T Cells Is Reversed by Vitamin E Supplementation

Marko

Ahmed

Bunnell

et al. 2007

The Journal of Immunology

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Aging is associated with reduced IL-2 production and T cell proliferation. Vitamin E supplementation, in aged animals and humans, increases cell division and IL-2 production by naive T cells. The immune synapse forms at the site of contact between a T cell and an APC and participates in T cell activation. We evaluated whether vitamin E affects the redistribution of signaling proteins to the immune synapse. Purified CD4+ T cells, from the spleens of young and old mice, were treated with vitamin E before stimulation with a surrogate APC expressing anti-CD3. Using confocal fluorescent microscopy, we observed that CD4+ T cells from old mice were significantly less likely to recruit signaling proteins to the immune synapse than cells from young mice. Vitamin E increased the percentage of old CD4+ T cells capable of forming an effective immune synapse. Similar results were found following in vivo supplementation with vitamin E. When compared with memory cells, naive T cells from aged mice were more defective in immune synapse formation and were more responsive to vitamin E supplementation. These data show, for the first time, that vitamin E significantly improves age-related early T cell signaling events in naive CD4+ T cells.

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Age-Related Decreases in IL-2 Production by Human T Cells Are Associated with Impaired Activation of Nuclear Transcriptional Factors AP-1 and NF-AT

Cited by 109 publications

References 0 publications

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

Single-Cell Analyses Reveal Two Defects in Peptide-Specific Activation of Naive T Cells from Aged Mice

Age-Associated Decline in Effective Immune Synapse Formation of CD4+ T Cells Is Reversed by Vitamin E Supplementation

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