Vγ9+ γδ T cells in systemic sclerosis patients are numerically and functionally preserved and induce fibroblast apoptosis

Bendersky, Anna; Markovits, Noa; Bank, Ilan

doi:10.1016/j.imbio.2009.05.012

Cited by 18 publications

(23 citation statements)

References 51 publications

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“…Together with our findings, g/ d T cells have effects of enhance collagen synthesis in fibroblasts without direct cell contact. In contrast, recently, Bendersky et al reported Vg9 + T cells were equally and persistently represented in SSc patients at levels similar to healthy controls, and they preserved the ability to respond to the classical Vg9 + T cell auto-antigen isopentenyl pyrophosphate and to execute disruption of fibroblast growth and induction of apoptotic death with contact-dependent manner [30]. While the reason for the discrepancy among the reports is unclear, it might be due to the physical contact between g/d T cells and fibroblasts, which may influence a different response pattern.…”

Section: Discussionmentioning

confidence: 87%

Circulating γ/δ T cells in systemic sclerosis exhibit activated phenotype and enhance gene expression of proalpha2(I) collagen of fibroblasts

Ueda‐Hayakawa

Hasegawa

Hamaguchi

et al. 2013

Journal of Dermatological Science

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Section: Discussionmentioning

confidence: 87%

Circulating γ/δ T cells in systemic sclerosis exhibit activated phenotype and enhance gene expression of proalpha2(I) collagen of fibroblasts

Ueda‐Hayakawa

Hasegawa

Hamaguchi

et al. 2013

Journal of Dermatological Science

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“…PBMC and synovial fluid mononuclear cells (SFMC) were isolated by Ficoll Hypaque (Sigma-Aldrich, St. Louis, MO) density centrifugation as previously described (15).…”

Section: Isolation Of Mononuclear Cellsmentioning

confidence: 99%

“…Primary fibroblastic lines were obtained from SF removed from knees of patients for therapeutic indications and maintained as previously described (15). In brief, fibroblasts were derived by culturing adherent synovial fluid cells in plastic wells in DMEM-supplemented medium for 48 h followed by removal of all of the nonadherent cells.…”

Section: Fibroblast Culturesmentioning

confidence: 99%

“…FITC, allophycocyanin, PerCP, or PE-conjugated nonbinding Ig isotype control mAb (BD Pharmingen) or fluorochrome-conjugated mAb to CD4, CD3, CD25 (BD Pharmingen), or the human Vg9, Vd1, and Vd2 gene products (Immunotech) were added to a resuspended pellet of 2 3 10 5 mononuclear cells (MC) for 45 min on ice (15). Cells were then washed in PBS (pH 7.4; Life Technologies, Invitrogen).…”

Section: Characterization Of T Cell Subsets By Flow Cytometrymentioning

confidence: 99%

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Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Bendersky

Marcu-Malina

Berkun

et al. 2012

The Journal of Immunology

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The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9+Vδ2+ (Vγ9+) T cells, in JIA. We found that as opposed to CD4+ T cells, equally high percentages (∼35%) of Vγ9+ T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2+ T cells, similarly amplified cytokine secretion by SF and PB Vγ9+ T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9+ T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9+ T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4+CD25+FOXP3+ cells (regulatory T cells). Furthermore, coculture with the Vγ9+ T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9+ T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

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“…While abnormal responses to conventional peptidic autoantigens have been identified, a few studies suggest that abnormal responses to lipid antigens and phosphoantigens may also play a role in the pathogenesis of SSc (4, 5). In this regard, γδ T cells expressing the Vδ1 gene segment in their T cell receptor (TCR) (Vδ1 + T cells) were found to be dysregulated in early and late SSc (6, 7).…”

Section: Introductionmentioning

confidence: 99%

Dysregulated CD25 and Cytokine Expression by γδ T Cells of Systemic Sclerosis Patients Stimulated With Cardiolipin and Zoledronate

et al. 2018

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Objectivesγδ T cells, a non-conventional innate lymphocyte subset containing cells that can be activated by lipids and phosphoantigens, are abnormally regulated in systemic sclerosis (SSc). To further evaluate the significance of this dysregulation, we compared how exposure to an autoantigenic lipid, cardiolipin (CL), during co-stimulation with an amino-bisphosphonate (zoledronate, zol), affects the activation and cytokine production of SSc and healthy control (HC) γδ T cells.MethodsExpression of CD25 on Vγ9+, Vδ1+, and total CD3+ T cells in cultured peripheral blood mononuclear cells (PBMCs), their binding of CD1d tetramers, and the effect of monoclonal antibody (mAb) blockade of CD1d were monitored by flow cytometry after 4 days of in vitro culture. Intracellular production of IFNγ and IL-4 was assessed after overnight culture.ResultsPercentages of CD25+ among CD3+ and Vδ1+ T cells were elevated significantly in short-term cultured SSc PBMC compared to HC. In SSc but not HC, CL and zol, respectively, suppressed %CD25+ Vγ9+ and Vδ1+ T cells but, when combined, CL + zol significantly activated both subsets in HC and partially reversed inhibition by the individual reagents in SSc. Importantly, Vδ1+ T cells in both SSc and HC were highly reactive with lipid presenting CD1d tetramers, and a CD1d-blocking mAb decreased CL-induced enhancement of %SSc CD25+ Vδ1+ T cells in the presence of zol. %IFNγ+ cells among Vγ9+ T cells of SSc was lower than HC cultured in medium, CL, zol, or CL + zol, whereas %IFNγ+ Vδ1+ T cells was lower only in the presence of CL or CL + zol. %IL-4+ T cells were similar in SSc and HC in all conditions, with the exception of being increased in SSc Vγ9+ T cells in the presence of CL.ConclusionAbnormal functional responses of γδ T cell subsets to stimulation by CL and phosphoantigens in SSc may contribute to fibrosis and immunosuppression, characteristics of this disease.

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Vγ9+ γδ T cells in systemic sclerosis patients are numerically and functionally preserved and induce fibroblast apoptosis

Cited by 18 publications

References 51 publications

Circulating γ/δ T cells in systemic sclerosis exhibit activated phenotype and enhance gene expression of proalpha2(I) collagen of fibroblasts

Circulating γ/δ T cells in systemic sclerosis exhibit activated phenotype and enhance gene expression of proalpha2(I) collagen of fibroblasts

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Dysregulated CD25 and Cytokine Expression by γδ T Cells of Systemic Sclerosis Patients Stimulated With Cardiolipin and Zoledronate

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