Mutations in T cell Receptor ζ Chain mRNA of Peripheral T cells from Systemic Lupus Erythematosus Patients

Tsuzaka, Kensei; Takeuchi, Tsutomu; Onoda, Noboru; Pang, Mao; Abe, Tohru

doi:10.1006/jaut.1998.0223

Cited by 55 publications

(51 citation statements)

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“…We and other groups have reported that a decrease in tyrosine phosphorylation and the diminished expression of the TCR -chain ( ) in the peripheral blood T cells (PBTs) of SLE patients may be responsible for the pathogenesis of SLE (5)(6)(7). SLE patients have several alterations in the mRNA open reading frame (8). We previously reported the aberrant form of mRNA lacking exon 7 ( mRNA/exon 7Ϫ) observed in SLE patients (5).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

Tsuzaka

Nozaki

Kumazawa

et al. 2006

The Journal of Immunology

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We have reported that the TCRζ mRNA with alternatively spliced 3′ UTR (ζ mRNA/as-3′-untranslated region (UTR)) and ζ mRNA lacking exon 7 (ζ mRNA/exon 7−) observed in systemic lupus erythematosus patient T cells can lead to down-regulation of both ζ and TCR/CD3 complexes. To determine whether these T cells expressing decreased ζ exhibit differential transcription patterns, we transfected retrovirus vectors containing wild-type ζ cDNA, ζ cDNA/as-3′ UTR, and ζ cDNA/exon 7− into murine T cell hybridoma MA5.8 cells which lack ζ expression to construct the MA5.8 mutants WT, AS3′ UTR, and EX7−, respectively. FACS analyses demonstrated reduced cell surface expression of ζ and TCR/CD3 complexes on the AS3′ UTR mutant and the EX7− mutant in comparison to that on the WT mutant. Total RNA was collected after stimulating the MA5.8 mutants with anti-CD3 Ab. Reverse-transcribed cDNA was applied to the mouse cDNA microarray containing 8691 genes, and the results were confirmed by real-time PCR. The results showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-β2, were down-regulated in both the AS3′ UTR mutant and the EX7− mutant. Another 16 genes were up-regulated in both, and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus receptor-related 2, syndecan-1, and granzyme A. Increased protein expression of these genes was confirmed by Western blot and FACS analyses. Identification of these responsive genes in T cells in which the ζ and TCR/CD3 complexes were down-regulated may help to better understand the pathogenesis of systemic lupus erythematosus.

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Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

“…Whole mRNA was isolated from 2B4.11 cells and converted to whole cDNA with reverse transcriptase according to a previously described method (8). The whole cDNA was quantified and used as the template DNA standard for real-time PCR.…”

Section: Preparation Of the Template Dna For Real-time Pcrmentioning

confidence: 99%

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

Tsuzaka

Nozaki

Kumazawa

et al. 2006

The Journal of Immunology

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“…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)(3)(4) and that this defect persists over time and is independent of disease activity (5).…”

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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

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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“…Recently, an alternatively spliced isoform of the chain with an insertion of glutamine at position 100, that is expressed equally in normal and SLE T cells, has been described (12,33). Expression of alternatively spliced isoforms of the chain with insertion or deletion of various exons or combinations of exons in SLE T cells has been reported (7,11,12,34). Although abnormalities in the expression of the detergent-soluble 16-kd form of the chain have been found in SLE, a complete spectrum of the expression of different forms of the TCR chain has not been reported.…”

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confidence: 99%

Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus

Nambiar

Enyedy

Fisher

et al. 2002

Arthritis & Rheumatism

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Mutations in T cell Receptor ζ Chain mRNA of Peripheral T cells from Systemic Lupus Erythematosus Patients

Cited by 55 publications

References 0 publications

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

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

Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus

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