Molecular Basis of Deficient IL-2 Production in T Cells from Patients with Systemic Lupus Erythematosus

Solomou, Elena E.; Juang, Yuang-Taung; Gourley, Mark F.; Kammer, Gary M.; Tsokos, George C.

doi:10.4049/jimmunol.166.6.4216

Cited by 183 publications

(195 citation statements)

References 29 publications

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“…We first transfected primary human T and Jurkat cells, using a cell electroporation technique (11)(12)(13)(14), either with the plasmid-encoding cDNA (pcDNA)/Elf-1 plasmid, which encodes the full-length Elf-1 cDNA, or with the empty plasmid to establish the protein products of the Elf-1 gene. The cytoplasmic extracts from primary ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The isolation and purification of primary T lymphocytes and culture of Jurkat cells have been recently described (11,12).…”

Section: Lymphocyte Isolation and Cell Culturementioning

confidence: 99%

“…The electroporation methods used for the transfection of Jurkat and primary T lymphocytes recently have been described (11)(12)(13)(14).…”

Section: Transfection Of Primary Human Lymphocytesmentioning

confidence: 99%

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Phosphorylation and O-Linked Glycosylation of Elf-1 Leads to Its Translocation to the Nucleus and Binding to the Promoter of the TCR ζ-Chain

Juang

Solomou

Rellahan

et al. 2002

The Journal of Immunology

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Elf-1, a member of the E 26-specific transcription factor family with a predicted molecular mass of 68 kDa, is involved in the transcriptional regulation of several hematopoietic cell genes. We demonstrate that Elf-1 exists primarily as a 98-kDa form in the nucleus and as an 80-kDa form in the cytoplasm. Phosphorylation and O-linked glycosylation contribute to the increased posttranslational molecular mass of Elf-1. The 98-kDa Elf-1 is released from the cytoplasm tethering retinoblastoma protein and moves to the nucleus, where it binds to the promoter of the TCR ζ-chain gene. Finally, the cytoplasmic 98-kDa form enters the proteasome pathway and undergoes degradation. In conclusion, different forms of Elf-1 are the products of posttranslational modifications that determine its subcellular localization, activity, and metabolic degradation.

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Section: Resultsmentioning

confidence: 99%

“…The isolation and purification of primary T lymphocytes and culture of Jurkat cells have been recently described (11,12).…”

Section: Lymphocyte Isolation and Cell Culturementioning

confidence: 99%

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Phosphorylation and O-Linked Glycosylation of Elf-1 Leads to Its Translocation to the Nucleus and Binding to the Promoter of the TCR ζ-Chain

Juang

Solomou

Rellahan

et al. 2002

The Journal of Immunology

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“…Interleukin-2 (IL-2) production in SLE T cells is decreased because of limited transcriptional activity of the IL-2 promoter due to increased expression of the repressor cAMP response element modulator (CREM) (9) and decreased expression of the p65 chain of nuclear factor B (NF-B), which leads to decreased NF-B activity (10). Our group recently demonstrated that substitution of the defective p65 subunit of NF-B enhanced TCR/CD3-mediated IL-2 production in SLE T cells (11).…”

mentioning

confidence: 99%

Reconstitution of deficient T cell receptor ζ chain restores T cell signaling and augments T cell receptor/CD3–induced interleukin‐2 production in patients with systemic lupus erythematosus

Nambiar

Fisher

Warke

et al. 2003

Arthritis & Rheumatism

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103

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Objective. T cells from a majority of patients with systemic lupus erythematosus (SLE) display antigen receptor-mediated signaling aberrations associated with defective T cell receptor (TCR) chain, a subunit of the TCR/CD3 complex. This study was undertaken to explore the possibility that forced expression of TCR chain may reverse the known signaling abnormalities and defective interleukin-2 (IL-2) production in SLE T cells.Methods. Freshly isolated SLE T cells were transfected with TCR chain construct in a eukaryotic expression vector at high efficiency, by a recently developed nucleoporation technique. Restoration of TCR/ CD3-mediated signaling was studied in the chaintransfected cells.Results. In SLE T cells transfected with TCR chain, surface expression of TCR chain was increased and the TCR/CD3-induced increased free intracytoplasmic calcium concentration response was normalized, as was hyperphosphorylation of cellular substrates. Simultaneously, the previously noted increased expression of the Fc receptor ␥ chain was diminished in SLE T cells transfected with the chain expression vector, and the surface membrane clusters of cell signaling molecules were redistributed to a more continuous pattern. TCR chain replacement also augmented the expression of diminished TCR/CD3-mediated IL-2 production in SLE T cells, associated with increased expression of the p65 subunit of nuclear factor B in the nuclear fractions of these T cells. Conclusion. These results suggest that reconstitution of deficient TCR chain can reverse the TCR/ CD3-mediated signaling abnormalities as well as the defective IL-2 production in T cells of patients with SLE.It is well recognized that T cells from patients with systemic lupus erythematosus (SLE) display a number of signaling abnormalities (1). Many of the identified molecular aberrations explain certain established cell and cytokine defects, whereas the mechanisms of other defects have not yet been elucidated. Our group and others have demonstrated that the expression of the subunit of the T cell receptor (TCR) is decreased in a majority of SLE patients (2-4) and that this defect persists over time and is independent of disease activity (5).Despite the decreased expression of the TCR chain in SLE T cells, crosslinking of the TCR/CD3 complex leads to increased free intracytoplasmic calcium concentration ([Ca 2ϩ ] i ) response (6) and protein tyrosine phosphorylation (2,4). These events appear to occur because the Fc receptor (FcR) ␥ chain becomes a functional part of the TCR/CD3 complex (7). In support

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“…56 More recently, increased binding of a transcriptional inhibitor of IL-2 gene promoter, phosphorylated cAMP response element modifier (pCREM), in lupus T cells has been shown to underpin reduced IL-2 production. 57 Further, a defect involving Cbl, an adaptor protein that negatively regulates transmembrane signalling, has been shown. This abnormality has been suggested to underpin persistent hyperexpression of CD40 ligand (CD40L)L and resistance to tolerance induction.…”

Section: T-lymphocyte and Natural Killer (Nk) Cellmentioning

confidence: 99%

Immunopathology and the gene therapy of lupus

Mageed

Prud’homme

2003

Gene Ther

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Molecular Basis of Deficient IL-2 Production in T Cells from Patients with Systemic Lupus Erythematosus

Cited by 183 publications

References 29 publications

Phosphorylation and O-Linked Glycosylation of Elf-1 Leads to Its Translocation to the Nucleus and Binding to the Promoter of the TCR ζ-Chain

Phosphorylation and O-Linked Glycosylation of Elf-1 Leads to Its Translocation to the Nucleus and Binding to the Promoter of the TCR ζ-Chain

Reconstitution of deficient T cell receptor ζ chain restores T cell signaling and augments T cell receptor/CD3–induced interleukin‐2 production in patients with systemic lupus erythematosus

Immunopathology and the gene therapy of lupus

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