Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of ζ-chains and p59fyn/p56lck in human T cells

Whisler, Ronald L.; Chen, Ming; Beiqing, Liu; Newhouse, Yvonne G.

doi:10.1016/s0047-6374(99)00074-3

Cited by 28 publications

(18 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, an age-associated alteration in TCR signaling (a pathway which was not profiled in the prior study, see Table 2) is consistent with published reports [20]. In fact, recent work has demonstrated that there is an age-associated decline in TCR-induced Erk phosphorylation in naïve Th cells, but no age associated difference in other TCR-induced responses including ZAP70 in naïve Th cells, and no age-associated difference for TCR-induced responses in memory Th cells [21].…”

Section: Resultssupporting

confidence: 90%

High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors

et al. 2014

View full text Add to dashboard Cite

BackgroundSingle-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors.MethodsIn the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25–40 yrs)].ResultsAssociations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets.ConclusionsThese results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies.

show abstract

Section: Resultssupporting

confidence: 90%

High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In evaluating T cell signal transduction machinery, investigators have demonstrated that cells from healthy aged mice and humans manifest several defects in early kinase activation, calcium mobilization, and transcription factor generation (142,401). The molecular basis for the decline in signaling events is largely unresolved, although it is recognized that the contribution of ROS is rather high.…”

Section: Cd28mentioning

confidence: 99%

Aging and Immune Function: Molecular Mechanisms to Interventions

Ponnappan

2011

Antioxidants & Redox Signaling

290

266

View full text Add to dashboard Cite

The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed ''immune senescence,'' manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFkB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551-1585.

show abstract

“…Moreover, TCR signaling is also weakened with aging. It was indeed shown that ZAP-70 activation in response to CD3-TCR stimulation is reduced in naïve CD4 + T cells from elderly humans and leads to decreased tyrosine phosphorylation of the ζ-chains [48]. In fact, the impaired ZAP-70 activation with aging is independent of the CD4 + phenotype and occurs in memory as well as naïve CD4 + T cells [48].…”

Section: Age-associated Intrinsic Defects In Cd4+ T Cell Functionsmentioning

confidence: 99%

“…It was indeed shown that ZAP-70 activation in response to CD3-TCR stimulation is reduced in naïve CD4 + T cells from elderly humans and leads to decreased tyrosine phosphorylation of the ζ-chains [48]. In fact, the impaired ZAP-70 activation with aging is independent of the CD4 + phenotype and occurs in memory as well as naïve CD4 + T cells [48]. Downstream events of ZAP-70 activation include cytoskeleton remodeling, an important aspect of multiple essential functions of T cells such as cell migration, cytokine secretion, receptor endocytosis and many more.…”

Section: Age-associated Intrinsic Defects In Cd4+ T Cell Functionsmentioning

confidence: 99%

Aging of the CD4 T Cell Compartment

Lefebvre

Haynes

2012

TOLSJ

View full text Add to dashboard Cite

Higher morbidity and mortality following infections, particularly influenza, is observed in the elderly population. Because of this, people over 65 years old are often targeted for preventive immunization. Many vaccines, however, are not as effective in generating protective antibodies in older individuals. CD4+ T cells, through their B cell helper functions, play a central role in the humoral response. Aging has deleterious effects on the immune system, and understanding how aging impairs CD4+ T cell functions is of critical importance to design new immunization and treatment strategies targeted to the elderly population. In this paper, we review some of the qualitative and quantitative changes in the CD4+ T cell compartment that arise with aging. We also summarize the age-related intrinsic defects that impact naïve, memory and regulatory CD4+ T cell functions.

show abstract

Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of ζ-chains and p59fyn/p56lck in human T cells

Cited by 28 publications

References 51 publications

High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors

High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors

Aging and Immune Function: Molecular Mechanisms to Interventions

Aging of the CD4 T Cell Compartment

Contact Info

Product

Resources

About