Impaired suppression of synovial fluid CD4+CD25− T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells

Haufe, Sabine; Haug, Markus; Schepp, Carsten P.; Kuemmerle‐Deschner, Jasmin; Hansmann, Sandra; Rieber, Nikolaus; Tzaribachev, Nikolay; Hospach, Toni; Maier, Jan; Dannecker, Guenther E.; Holzer, Ursula

doi:10.1002/art.30503

Cited by 76 publications

(77 citation statements)

References 33 publications

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“…Given the suppressive phenotype of RA SF Tregs, we hypothesized that the reduced suppression might be due to a resistance of RA SF responder T cells to suppression by Tregs, rather than impaired capacity of the Tregs. This view is consistent with studies performed in JIA SF, where crossover studies demonstrated that reduced Treg suppression was due to resistance of responder cells to suppression rather than defective Tregs (56,57). However, this contrasts with previous studies showing that Tregs from the blood of RA patients were inherently defective in their suppressive capacity (6,7,9).…”

Section: Discussionsupporting

confidence: 87%

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

Basdeo

Moran

Cluxton

et al. 2015

The Journal of Immunology

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In autoimmune diseases such as rheumatoid arthritis (RA), regulatory T cells (Tregs) fail to constrain autoimmune inflammation; however, the reasons for this are unclear. We investigated T cell regulation in the RA joint. Tregs from RA synovial fluid suppressed autologous responder T cells; however, when compared with Tregs from healthy control peripheral blood, they were significantly less suppressive. Despite their reduced suppressive activity, Tregs in the RA joint were highly proliferative and expressed FOXP3, CD39, and CTLA-4, which are markers of functional Tregs. This suggested that the reduced suppression is due to resistance of RA synovial fluid responder T cells to Treg inhibition. CD161+ Th17 lineage cells were significantly enriched in the RA joint; we therefore investigated their relative susceptibility to Treg-mediated suppression. Peripheral blood CD161+ Th cells from healthy controls were significantly more resistant to Treg-mediated suppression, when compared with CD161- Th cells, and this was mediated through a STAT3-dependant mechanism. Furthermore, depletion of CD161+ Th cells from the responder T cell population in RA synovial fluid restored Treg-mediated suppression. In addition, CD161+ Th cells exhibited pathogenic features, including polyfunctional proinflammatory cytokine production, an ability to activate synovial fibroblasts, and to survive and persist in the inflamed and hypoxic joint. Because CD161+ Th cells are known to be enriched at sites of autoinflammation, our finding that they are highly proinflammatory and resistant to Treg-mediated suppression suggests an important pathogenic role in RA and other autoimmune diseases.

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Section: Discussionsupporting

confidence: 87%

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

Basdeo

Moran

Cluxton

et al. 2015

The Journal of Immunology

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“…31,32 Indeed, as described above, high levels of T REG cells are present in the inflamed joints of patients with arthritis and numerous publications have shown that synovial fluid T REG cells are functional in vitro. 6,7,[33][34][35][36] Nevertheless, the proinflammatory environment might interfere with their effectiveness at the site of inflammation. For example, highly activated APCs in inflamed joints might reduce T REG -cell function, as strong and prolonged T-cell stimulation through the concomitant stimulation of the T-cell receptor and CD28 signalling pathways can impair T REG -cell-mediated suppression.…”

Section: T Reg Cells In Autoimmune Inflammationmentioning

confidence: 99%

“…Interestingly, this finding is not a result of a functional defect in synovial fluid T REG cells, as these cells suppressed effector T cells isolated from the peripheral blood to a similar level as was observed in healthy controls. 6,7 Instead effector T cells from the site of inflammation showed reduced responsiveness to suppression, which, although not associated with a memory phenotype of the cells, did (1) and induce resistance of effector T cells (2). In the presence of proinflammatory APCs, a small population of unstable T REG cells might convert into pathogenic effector T cells (3).…”

Section: Resistance Of Effector T Cellsmentioning

confidence: 99%

“…correlate with their activation status. 6,7 More specifically, we established that protein kinase B (PKB) hyperactivation contributed to resistance of synovial fluid T effector cells to suppression. In our opinion, PKB hyperactivation results from the proinflammatory synovial environment, because TNF and IL-6, both highly present in inflamed joints, induce PKB activation and subsequent resistance to suppression in effector T cells from healthy donors.…”

Section: Resistance Of Effector T Cellsmentioning

confidence: 99%

“…5 In particular, findings in 2011 indicated that resistance of effector T cells to suppression has an important role in synovial inflammation. 6,7 In addition, insights into T-cell plasticity, especially in inflamed joints, 8,9 have extended our understanding of autoimmune pathology. Here we summarize our current knowledge on how T cells lose control in autoimmune inflammation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

T cells out of control—impaired immune regulation in the inflamed joint

2012

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Since the discovery of FOXP3+ regulatory T (T(REG)) cells over 15 years ago, intensive research has focused on their presence, phenotype and function in autoimmune disease. Whether deficiencies in T(REG) cells underlie autoimmune pathology and whether, or how, therapeutic approaches based on these cells might be successful is still the subject of debate. The potential role of T(REG)-cell extrinsic factors, such as proinflammatory cytokines and resistance of effector T cells to suppression, as the cause of regulatory defects in chronic autoimmune inflammation is an intensive area of research. It is now clear that, at the site of inflammation, antigen presenting cells (APCs) and proinflammatory cytokines drive effector T cell skewing and plasticity, and that these T cells can become unresponsive to regulation. In addition, expansion and function of T(REG) cells is affected by the inflammatory environment; indeed, new data suggest that, in certain conditions, T(REG) cells promote inflammation. This Review summarizes the latest findings on changes in effector T cell homeostasis in autoimmune disease and focuses on how mechanisms that normally regulate these cells are affected in the inflamed joints of patients with arthritis. These findings have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.

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Editorial: Quality or quantity? Unraveling the role of Treg cells in rheumatoid arthritis

Prakken¹,

Wehrens²,

Wijk³

2013

Arthritis & Rheumatism

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Impaired suppression of synovial fluid CD4+CD25− T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells

Cited by 76 publications

References 33 publications

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

T cells out of control—impaired immune regulation in the inflamed joint

Editorial: Quality or quantity? Unraveling the role of Treg cells in rheumatoid arthritis

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