MRL/Mp CD4+,CD25− T cells show reduced sensitivity to suppression by CD4+,CD25+ regulatory T cells in vitro: A novel defect of T cell regulation in systemic lupus erythematosus

Monk, Clare R.; Spachidou, Maria P.; Rovis, Flavia; Leung, Eva; Botto, Marina; Lechler, Robert I.; Garden, Oliver A.

doi:10.1002/art.20976

Cited by 123 publications

(118 citation statements)

References 17 publications

(18 reference statements)

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“…Some previous studies demonstrated that MRL/lpr mice possessed a normal percentage of Treg cells (35,36). Reports focusing on the suppressive function of Treg cells from MRL/lpr mice were inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Hou¹,

He²,

Li³

et al. 2011

Arthritis & Rheumatism

106

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Objective. SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice.Methods. In vitro, the effects of SM934 on the activation of polyclonal CD4؉ T cells and the differentiation of naive CD4؉ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease.Results In female MRL/lpr mice, an autoimmune syndrome develops spontaneously that closely resembles human systemic lupus erythematosus (SLE) and is characterized by the production of various autoantibodies and the development of fatal glomerulonephritis (1,2).Disease begins as early as 8 weeks of age in these mice, with the presence of detectable serum autoantibodies. Pronounced lymphadenopathy is observed at 12 weeks of age, which is largely attributable to the accumulation of a population of B220ϩ and CD3ϩ cells that are mostly CD4Ϫ and CD8Ϫ (double-negative T cells). By 12-16 weeks of age, MRL/lpr mice begin to produce a variety of autoantibodies, including antidouble-stranded DNA (anti-dsDNA) antibodies. Multiple organs are affected, and a steady deterioration of renal function manifesting as severe proteinuria begins at approximately 16 weeks of age. From 16 weeks of age to 24 weeks of age, proliferative immune complex-

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Section: Discussionmentioning

confidence: 99%

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Hou¹,

He²,

Li³

et al. 2011

Arthritis & Rheumatism

106

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“…Interestingly, a significantly reduced level of Treg has also been observed to correlate with autoantibody production and the onset of a lupus-like disease in different murine models (18,19). However, analysis of the role of Treg in human autoimmunity during ongoing disease has been hampered by a lack of specific antibodies, because all available Treg-"specific" surface markers (CD25, CTLA-4, glucocorticoid-induced tumor necrosis factor [TNF] receptor) can also be expressed on nonsuppressive activated T cells.…”

mentioning

confidence: 99%

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Franz¹,

Fritzsching²,

Riehl³

et al. 2007

Arthritis & Rheumatism

122

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Objective. To define the phenotype and function of CD4؉,CD25؉ regulatory T cells (Treg) in patients with cutaneous lupus erythematosus (CLE), a heterogeneous autoimmune disease characterized primarily by inflammatory skin lesions.Methods. The number of Treg in skin specimens obtained from patients with various subtypes of CLE was investigated by immunohistochemical analysis, using anti-Foxp3 and anti-CD4 monoclonal antibodies. Furthermore, characterization of peripheral blood CD4؉,CD25؉ Treg from normal healthy donors and patients with CLE was carried out by flow cytometry, analyzing the expression of Foxp3 and Treg subpopulations. We also purified CD4؉,CD25 high Treg obtained from patients with CLE and tested the sensitivity of these cells to CD95L-mediated apoptosis.Results. Quantitative analysis of CD4؉ T cells in skin lesions from patients with CLE revealed that the number was similar to that in lesions from patients with other chronic inflammatory diseases, but the number of Foxp3؉ Treg in CLE was significantly reduced. There was no correlation between disease subtype and the frequency of Foxp3؉ Treg in the skin of patients with CLE. In peripheral blood, no significant differences were observed in the number and phenotype of CD4؉,CD25؉ Treg or in the sensitivity to apoptosis of CD4؉,CD25 high Treg derived from patients with CLE and those derived from normal healthy donors.Conclusion. These data suggest that an organspecific abnormality of Treg in the skin underscores the importance of analyzing Treg in the affected tissue. Such a local process might give insight into the pathogenic mechanisms of CLE and differs from a global peripheral dysfunction as reported for patients with a systemic manifestation of the disease.

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“…In the presence of wild-type control (MRL/+) Teff, MRL/lpr Treg were just as potent as the MRL/+ Treg in suppressing the normal Teff proliferative responses, division and cytokine production. Monk et al showed previously that MRL/+ Teff were insensitive to the cross-strain (CBA/Ca) Treg-mediated suppression on their proliferative responses to anti-CD3/CD28 mAb stimulation in an in vitro system in the absence of APC [34]. In the presence of APC, however, we demonstrated here that MRL/+ Teff upon anti-CD3 mAb stimulation were very sensitive to the syngeneic MRL/+ or MRL/lpr Treg-mediated suppression, which could be completely overridden by providing the anti-CD28 mAb costimulation.…”

Section: Discussionmentioning

confidence: 99%

“…These studies demonstrated a reduced frequency or a loss of functions of the CD4 + CD25 hi T cell population in SLE patients [16-18, 32, 33]. In addition, a low Treg frequency or reduced sensitivity of effector T cells (Teff) to Tregmediated suppression was also described in lupus mice [15,34]. These findings suggest a potential role of Treg in SLE.…”

Section: Introductionmentioning

confidence: 95%

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

et al. 2008

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Regulatory T cell deficiency is evident in patients with lupus, but the casual relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic agedependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.

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MRL/Mp CD4+,CD25− T cells show reduced sensitivity to suppression by CD4+,CD25+ regulatory T cells in vitro: A novel defect of T cell regulation in systemic lupus erythematosus

Abstract: Objective. To investigate the hypothesis that loss of suppression mediated by peripheral CD4؉,CD25؉ regulatory T cells is a hallmark of systemic lupus erythematosus (SLE).

Cited by 123 publications

References 17 publications

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

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