Premature senescence of T-cell subsets in axial spondyloarthritis

Fessler, Johannes; Raicht, Andrea; Husic, Rusmir; Ficjan, Anja; Duftner, Christina; Schwinger, Wolfgang; Dejaco, Christian; Schirmer, Michael

doi:10.1136/annrheumdis-2014-206119

Cited by 32 publications

(22 citation statements)

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“…As telomerase activity depends on the expression of CD28, it decreases with CD28 reduction and could explain the shortened telomere length in CD4 + CD28 − T cells [ 48 ]. This phenomena have been studied in aged CD4 + T cells both in RA and axial spondyloarthritis (including AS) so far [ 51 , 52 ]. One could expect that loss of the most important costimulatory signal CD28 and a shortened telomere length result in anergy and apoptosis [ 5 , 53 ].…”

Section: Prevalence Oligoclonality and Early Ageing Of The Cd4 mentioning

confidence: 99%

The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

Maly

Schirmer

2015

Journal of Immunology Research

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103

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CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

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Section: Prevalence Oligoclonality and Early Ageing Of The Cd4 mentioning

confidence: 99%

The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

Maly

Schirmer

2015

Journal of Immunology Research

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103

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“…For instance, studies on HIV elucidated the link between chronic infection and telomere attrition in CD4 + and CD8 + T cells 23 24. The replicative senescence of T lymphocytes is not limited to HIV since it is broadly investigated in association with malignancies,25 autoimmune disorders26 and environmental mediators 27 28. In autoimmune diseases, telomere erosion in lymphocytes has been less well delineated.…”

Section: Discussionmentioning

confidence: 99%

Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout

et al. 2017

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Vazirpanah, N. et al. (2017) Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout. Annals of the Rheumatic Diseases, 76(7), pp. 1309-1315. (doi:10.1136/annrheumdis-2016-210538) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/139064/ Abstract:Aim and background: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout.Methods: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New-Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4 + and CD8 + T lymphocytes, B lymphocytes, monocytes, natural killer (NK) cells and plasmacytoid dendritic cells (pDCs). Additionally, we assessed the potential temporal difference in TL and telomerase activity.Results: TL in PBMCs of healthy donors decreased over time reflecting normal ageing. Patients with gout demonstrated shorter telomeres (P=0.001, R 2 =0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age as compared to healthy counterparts at any age (P<0.0001, R 2 =0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (P=0.001). TL was inversely associated with the number of gouty flares (P=0.005).Conclusions: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares, and with cardiovascular disease in people with gout.

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“…Telomere lengths were measured using DNA from PBMCs as well as T-cell subsets by quantitative real-time PCR analysis and LightCycler FastStart DNA Master SYBR Green I (Roche, Vienna, Austria) as previously described (24). …”

Section: Methodsmentioning

confidence: 99%

Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis

et al. 2017

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ObjectivePremature senescence of lymphocytes is a hallmark of inflammatory rheumatic diseases such as rheumatoid arthritis (RA). Early T-cell aging affects conventional T-cells but is presumably not limited to this cell population; rather it might also occur in the regulatory T-cells (Tregs) compartment. In RA, Tregs fail to halt aberrant immune reactions and disease progression. Whether this is associated with early Treg senescence leading to phenotypic and functional changes of this subset is elusive so far.MethodsEighty-four RA patients and 75 healthy controls were prospectively enrolled into the study. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed for phenotypic and functional analyses of Treg subsets. T-cell receptor excision circle (TREC) levels and telomere lengths were determined using RT-PCR.ResultsIn this paper, we describe the novel CD4+FoxP3+CD28− T-cell subset (CD28− Treg-like cells) in RA patients revealing features of both Tregs and senescent T-cells: Treg surface/intracellular markers such as CD25, CTLA-4, and PD-1 as well as FOXP3 were all expressed by CD28− Treg-like cells, and they yielded signs of premature senescence including reduced TREC levels and an accumulation of γH2AX. CD28− Treg-like could be generated in vitro by stimulation of (CD28+) Tregs with TNF-α. CD28− Treg-like cells insufficiently suppressed the proliferation of effector T-cells and yielded a pro-inflammatory cytokine profile.ConclusionIn conclusion, we describe a novel T-cell subset with features of Tregs and senescent non-Tregs. These cells may be linked to an aberrant balance between regulatory and effector functions in RA.

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Premature senescence of T-cell subsets in axial spondyloarthritis

Cited by 32 publications

References 30 publications

The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout

Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis

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Premature senescence of T-cell subsets in axial spondyloarthritis

Cited by 32 publications

References 30 publications

The Story of CD4+CD28−T Cells Revisited: Solved or Still Ongoing?

The Story of CD4+CD28−T Cells Revisited: Solved or Still Ongoing?

Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout

Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis

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The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?