Abnormalities of T cell signaling in systemic lupus erythematosus

Moulton, Vaishali R.; Tsokos, George C.

doi:10.1186/ar3251

Cited by 168 publications

(153 citation statements)

References 65 publications

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“…Although there was no clear correlation between disease activity index scores or particular symptoms and Gal-1 levels, we hypothesized that low expression and diminished responsiveness of activated SLE T-cells to Gal-1 might contribute to immune regulatory dysfunction and enhanced T-cell activity in SLE pathology [17,29,34,35]. This assumption was supported by the finding that successful immunosuppressive therapy resulted in restoration of the level of Gal-1 as well as of the apoptotic sensitivity of SLE T-cells.…”

Section: Discussionsupporting

confidence: 67%

“…However, Gal-1 expression in pathological T-cells has not yet been specifically investigated. Dysregulated T-cell apoptosis in SLE has been well documented [17,29] and has been determined as one of the crucial defects in SLE pathogenesis. Hence, it is a plausible question whether Gal-1, acting on T-cells as a proapoptotic protein, is dysregulated in activated SLE T-cells and apoptotic sensitivity of these cells to exGal-1 is down-regulated thereby contributing to the pathomechanism of lupus.…”

Section: Diminished Gal-1 Expression Coincides With Decreased Exgal-1mentioning

confidence: 99%

“…T-cell dysfunction, including the malfunction of apoptosis is a major factor in SLE pathophysiology [17]. Although Gal-1 participates in the maintenance of immunohomeostasis by regulating T-cell functions and survival, its role in the lupus Tcell pathology has not yet been revealed.…”

Section: Introductionmentioning

confidence: 99%

“…Hence this mechanism shifts the immune response from the inflammatory Th1 to the Th2 direction [16]. of peripheral tolerance [17,18]. Lupus is characterized by immune-mediated inflammation in multiple organs and by the production of various autoantibodies [19].…”

Section: Introductionmentioning

confidence: 99%

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Novel role for galectin-1 in T-cells under physiological and pathological conditions

Deák¹,

Hornung²,

Novák³

et al. 2015

Immunobiology

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Secreted, extracellular galectin-1 (exGal-1) but not intracellular Gal-1 (inGal-1) has been described as a strong immunosuppressive protein due to its major activity of inducing apoptosis of activated T-cells. It has previously been reported that T-cells express Gal-1 upon activation, however its participation in T-cell functions has remained largely elusive. To determine function of Gal-1 expressed by activated Tcells we have carried out a series of experiments. We have shown that Gal-1, expressed in Gal-1-transgenic Jurkat cells or in activated T-cells, remained intracellularly indicating that Gal-1-induced T-cell death was not a result of an autocrine effect of the de novo expressed Gal-1. Rather, a particular consequence of the inGal-1 expression was that T-cells became more sensitive to exGal-1 added either as a soluble protein or bound to the surface of a Gal-1-secreting effector cell. This was also verified when the susceptibility of activated T-cells from wild type or Gal-1 knockout mice to Gal-1-induced apoptosis were compared. Murine T-cells expressing Gal-1 were more sensitive to the cytotoxicity of the exGal-1 than their Gal-1 knockout counterparts. We also conducted a study with activated T-cells from patients with systemic lupus erythematosus (SLE), a disease in which dysregulated T-cell apoptosis has been well described. SLE T-cells expressed lower amounts of Gal-1 than healthy T-cells and were less sensitive to exGal-1. These results suggested a novel role of inGal-1 in T-cells as a regulator of T-cell response to exGal-1, and its likely contribution to the mechanism in T-cell apoptosis deficiency in lupus.

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Section: Discussionsupporting

confidence: 67%

Section: Diminished Gal-1 Expression Coincides With Decreased Exgal-1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel role for galectin-1 in T-cells under physiological and pathological conditions

Deák¹,

Hornung²,

Novák³

et al. 2015

Immunobiology

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“…Following engagement of the T cell receptor (TCR), T cells from patients with SLE display rapid and enhanced calcium influx and phosphorylation of a wide range of cytoplasmic proteins [18]. These alterations have been linked to TCR rewiring, with replacement of CD3ζ by FcRγ and subsequent recruitment of Syk instead of the canonical ZAP-70 kinase [15].…”

Section: Surface and Intracellular Signaling In Sle T Cellsmentioning

confidence: 99%

T Cell Targeted Therapies in Lupus: Do They Make Sense?

Thanou

Merrill

2015

Curr Treat Options in Rheum

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Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Fan¹,

Liang²,

Tang³

et al. 2012

Arthritis & Rheumatism

100

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Objective. MicroRNAs (miRNAs) function to finetune the control of immune cell signaling. It is well established that there are abnormalities in the interleukin-2 (IL-2)-related signaling pathways in systemic lupus erythematosus (SLE). The miR-31 micro-RNA has been found to be markedly underexpressed in patients with SLE, and thus the present study was undertaken to investigate the role of miR-31 in IL-2 defects in lupus T cells.Methods. Expression levels of miR-31 were quantitated using TaqMan miRNA assays. Transfection and stimulation of cultured cells followed by TaqMan quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and reporter gene assays were conducted to determine the biologic function of miR-31. NF-AT nuclear translocation and expression were quantitatively measured using an ImageStream cytometer. Bioinformatics analysis, small interfering RNA (siRNA) knockdown, and Western blotting were performed to validate miR-31 targets and effects.Results. The expression of miR-31 was significantly decreased in lupus T cells, and this was positively correlated with the expression of IL-2. Overexpression of miR-31 in T cells increased the production of IL-2 by altering NF-AT nuclear expression and IL2 promoter activity, while knockdown of endogenous miR-31 reduced IL-2 production. RhoA expression was directly repressed by miR-31 in T cells. Of note, siRNA-mediated knockdown of RhoA enhanced IL2 promoter activity and, consequently, up-regulated IL-2 production. RhoA expression was consistently up-regulated and negatively correlated with the levels of miR-31 in lupus T cells. Manipulation of miR-31 expression in lupus T cells restored the expression of IL-2 at both the messenger RNA and protein levels.Conclusion. MicroRNA-31 is a novel enhancer of IL-2 production during T cell activation. Dysregulation of miR-31 and its target, RhoA, could be a novel molecular mechanism underlying the IL-2 deficiency in patients with SLE.Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder characterized by chronic

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Abnormalities of T cell signaling in systemic lupus erythematosus

Cited by 168 publications

References 65 publications

Novel role for galectin-1 in T-cells under physiological and pathological conditions

Novel role for galectin-1 in T-cells under physiological and pathological conditions

T Cell Targeted Therapies in Lupus: Do They Make Sense?

Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

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