Successful and Maladaptive T Cell Aging

Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1016/j.immuni.2017.03.010

Cited by 265 publications

(256 citation statements)

References 165 publications

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“…The failure in older individuals to generate appropriate adaptive immune responses cannot be attributed to a single major defect (Goronzy and Weyand, 2017; Nikolich-Zugich, 2018). Contrary to earlier predictions, the size and diversity of the human CD4 + T cell repertoire in older individuals is sufficient to respond to a diverse set of antigenic peptides (Qi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Defects in T cell activation because of reduced dendritic cell function or T cell receptor (TCR) signaling have been described (Li et al, 2012; Montgomery and Shaw, 2015) and may be overcome by adjuvanted vaccines or increasing the antigen dose (DiazGranados et al, 2014). The major T cell defect, however, appears to lie in cell differentiation and generation of T memory cells (Goronzy and Weyand, 2017). CD4 + T cell responses of older individuals are biased toward the generation of inflammatory effector T cells that undergo attrition, and long-lived memory cells fail to develop (Fang et al, 2016; Qi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Kim

Jadhav

et al. 2018

Cell Reports

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SUMMARY Induction of protective vaccine responses, governed by the successful generation of antigen-specific anti-bodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcrip-tome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling path-ways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Kim

Jadhav

et al. 2018

Cell Reports

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“…PPP shunting enables RA T-cells to ignore cell cycle checkpoints and become hyperproliferative. Proliferative pressure leads to premature T-cell aging and the acquisition of pro-inflammatory and tissue-invasive behavior [15]. In contrast, RA macrophages are overwhelmed by nutrient excess, become a victim of excessive glucose uptake and generate high levels of ATP and mitochondrial reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand

Zeisbrich

Goronzy

2017

Current Opinion in Immunology

113

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In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATPlow, NADPHhigh, ROSlow T-cells hyperproliferate and are forced into premature senescence. ATPhigh, ROShigh macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.

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“…‘Tissue‐seeding’ of T cells appears to occur early in childhood and shapes the TCR repertoire by exposure to environmental stimuli as well as respiratory infections . Nevertheless, T cells may also be able to survive for decades; this cellular repertoire may be shaped by epigenetic imprinting (for review see Goronzy and Weyand) in addition to tissue homing and TCR affinity for the nominal MHC class I/peptide epitope …”

Section: Homeostasis Of and Selection Pressure On Cmv‐directed T Cellsmentioning

confidence: 99%

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

et al. 2018

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Human cytomegalovirus (CMV) is a ubiquitous, persistent beta herpesvirus. CMV infection contributes to the accumulation of functional antigen-specific CD8 T-cell pools with an effector-memory phenotype and enrichment of these immune cells in peripheral organs. We review here this 'memory T-cell inflation' phenomenon and associated factors including age and sex. 'Collateral damage' due to CMV-directed immune reactivity may occur in later stages of life - arising from CMV-specific immune responses that were beneficial in earlier life. CMV may be considered an age-dependent immunomodulator and a double-edged sword in editing anti-tumour immune responses. Emerging evidence suggests that CMV is highly prevalent in patients with a variety of cancers, particularly glioblastoma. A better understanding of CMV-associated immune responses and its implications for immune senescence, especially in patients with cancer, may aid in the design of more clinically relevant and tailored, personalized treatment regimens. 'Memory T-cell inflation' could be applied in vaccine development strategies to enrich for immune reactivity where long-term immunological memory is needed, e.g. in long-term immune memory formation directed against transformed cells.

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Successful and Maladaptive T Cell Aging

Cited by 265 publications

References 165 publications

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

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