scholarly journals Interleukin-21 Receptor Gene Induction in Human T Cells Is Mediated by T-Cell Receptor-Induced Sp1 Activity

2005 ◽  
Vol 25 (22) ◽  
pp. 9741-9752 ◽  
Author(s):  
Zheng Wu ◽  
Hyoung-Pyo Kim ◽  
Hai-Hui Xue ◽  
Hong Liu ◽  
Keji Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Promoter Activity ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Small Interfering Rnas ◽  
Activated T Cells ◽  
Protein Levels ◽  
Interleukin 21

ABSTRACT Interleukin-21 (IL-21) plays important roles in regulating the immune response. IL-21 receptor (IL-21R) mRNA is expressed at a low level in human resting T cells but is rapidly induced by mitogenic stimulation. We now investigate the basis for IL21R gene regulation in T cells. We found that the −80 to −20 region critically regulates IL-21R promoter activity and corresponds to a major DNase I-hypersensitive site. Electrophoretic mobility shift assays, DNA affinity chromatography followed by mass spectrometry, and chromatin immunoprecipitation assays revealed that Sp1 binds to this region in vitro and in vivo. Moreover, mutation of the Sp1 motif markedly reduced IL-21R promoter activity, and Sp1 small interfering RNAs effectively diminished IL-21R expression in activated T cells. Interestingly, upon T-cell receptor (TCR) stimulation, T cells increased IL-21R expression and Sp1 protein levels while decreasing Sp1 phosphorylation. Moreover, phosphatase inhibitors that increased phosphorylation of Sp1 diminished IL-21R transcription. These data indicate that TCR-induced IL-21R expression is driven by TCR-mediated augmentation of Sp1 protein levels and may partly depend on the dephosphorylation of Sp1.

scholarly journals Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17

2004 ◽  
Vol 279 (50) ◽  
pp. 52762-52771 ◽  
Author(s):  
Xikui K. Liu ◽  
Xin Lin ◽  
Sarah L. Gaffen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Promoter Activity ◽  
Cell Receptor ◽  
Cross Linking ◽  
Supporting Evidence ◽  
Nuclear Factor ◽  
Tcr Signaling ◽  
Activated T Cells

The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To definecis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative promoter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal promoter, we created a series of 5′ truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this regionin vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

scholarly journals New Strategies in Engineering T-cell Receptor Gene-Modified T cells to More Effectively Target Malignancies

2015 ◽  
Vol 21 (23) ◽  
pp. 5191-5197 ◽  
Author(s):  
Thomas M. Schmitt ◽  
Ingunn M. Stromnes ◽  
Aude G. Chapuis ◽  
Philip D. Greenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
Cell Receptor ◽  
T Cell Receptor Gene ◽  
New Strategies ◽  
Cell Receptor Gene

251 THERAPY WITH T CELL RECEPTOR GENE MODIFIED T CELLS TARGETING HBsAg-PRODUCING HCC METASTASES

2013 ◽  
Vol 58 ◽  
pp. S107 ◽  
Author(s):  
W. Qasim ◽  
M. Brunetto ◽  
A. Gehring ◽  
S.-A. Xue ◽  
H. Zhan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
Cell Receptor ◽  
T Cell Receptor Gene ◽  
Cell Receptor Gene

scholarly journals HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Gene Therapy ◽  
2005 ◽  
Vol 12 (23) ◽  
pp. 1686-1695 ◽  
Author(s):  
L T van der Veken ◽  
M Hoogeboom ◽  
R A de Paus ◽  
R Willemze ◽  
J H F Falkenburg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Helper Activity ◽  
T Cell Receptor Gene ◽  
Cell Receptor Gene

S.100. SAP Augments Proximal T Cell Receptor Signal Strength Necessary for Restimulation-induced Apoptosis of Activated T Cells

2009 ◽  
Vol 131 ◽  
pp. S160 ◽  
Author(s):  
Andrew Snow ◽  
Rebecca Marsh ◽  
Scott Krummey ◽  
Philip Roehrs ◽  
Kejian Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Signal Strength ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Receptor Signal ◽  
S 100 ◽  
Induced Apoptosis

scholarly journals Promiscuous Behavior of HPV16E6 Specific T Cell Receptor Beta Chains Hampers Functional Expression in TCR Transgenic T Cells, Which Can Be Restored in Part by Genetic Modification

2010 ◽  
Vol 32 (1-2) ◽  
pp. 43-56
Author(s):  
Kirsten B. J. Scholten ◽  
Janneke J. Ruizendaal ◽  
Marcus Graf ◽  
Thomas Schoedl ◽  
Duco Kramer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
Careful Analysis ◽  
Cell Receptor ◽  
Open Reading Frames ◽  
Wild Type ◽  
Human T Cells ◽  
Reading Frames

Background: T cell receptor gene transfer is a promising strategy to treat patients suffering from HPV induced malignancies. Therefore we isolated the TCRαβ open reading frames of an HPV16E6 specific CTL clone and generated TCR transgenic T cells. In general low level expression of the transgenic TCR in recipient human T cells is observed as well as the formation of mixed TCRs dimers. Here we addressed both issues employing three different expression platforms.Methods: We isolated the HVP16E6 specific TCRα and TCRβ open reading frames and retrovirally transduced human T cells with either wild-type (wt), or codon-modified (cm) chains to achieve enhanced TCR expression levels, or used codon-modification in combination with cysteinization (cmCys) of TCRs to facilitate preferential pairing of the introduced TCRα and TCRβ chains.Results: Careful analysis of recipient T cells carrying the HPV16E6 TCRβ and endogenous TCR chains revealed the transgenic TCRβ chain to behave very promiscuously. Further analysis showed that the percentage of tetramer positive T cells in codon-modified/cysteinized TCR transgenic T cells was four-fold higher compared to wild-type and two-fold higher compared to codon-modification only. Functional activity, as determined by IFN-γ production, was high in cmCysTCR transgenic T cells, where it was low in cm and wt TCR transgenic T cells. Recognition of endogenously processed HPV16E6 antigen by cmCysTCR transgenic T cells was confirmed in a cytotoxicity assay.Conclusions: Promiscuous behavior of the HPV16E6 specific TCRβ chain can in part be forced back into specific action in TCR transgenic T cells by codon modification in combination with the inclusion of an extra cysteine in the TCR chains.

Defective Cytokine Expression but Adult-Type T-Cell Receptor, CD8, and p56lck Modulation in CD3− or CD2-Activated T Cells from Neonates

1995 ◽  
Vol 37 (1) ◽  
pp. 64-69 ◽  
Author(s):  
H Pirenne-Ansart ◽  
F Paillard ◽  
D De Groote ◽  
A Eljaafari ◽  
S Le Gac ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cytokine Expression ◽  
Activated T Cells ◽  
Adult Type
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