T-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse

2002 ◽  
Vol 109 (5) ◽  
pp. 758-770 ◽  
Author(s):  
Andre E. Nel
Keyword(s):  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Signal Integration ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Signaling Components

scholarly journals Molecular Characterization of a Fully Human Chimeric T-Cell Antigen Receptor for Tumor-Associated Antigen EpCAM

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Naoto Shirasu ◽  
Hiromi Yamada ◽  
Hirotomo Shibaguchi ◽  
Motomu Kuroki ◽  
Masahide Kuroki
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Antigen Receptor ◽  
Target Cells ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

The transduction of T cells to express chimeric T-cell antigen receptor (CAR) is an attractive strategy for adaptive immunotherapy for cancer, because the CAR can redirect the recognition specificity of T cells to tumor-associated antigens (TAAs) on the surface of target cells, thereby avoiding the limitations of HLA restriction. However, there are considerable problems with the clinical application of CAR, mostly due to its xenogeneic components, which could be immunogenic in humans. Moreover, while extensive studies on the CARs have been performed, the detailed molecular mechanisms underlying the activation of CAR-grafted T cells remain unclear. In order to eliminate potential immunogenicity and investigate the molecular basis of the CAR-mediated T-cell activation, we constructed a novel CAR (CAR57-28ζ) specific for one of the most important TAAs, epithelial cell adhesion molecule (EpCAM), using only human-derived genes. We revealed that in Jurkat T cells, lentivirally expressed CAR57-28ζ can transmit the T-cell-activating signals sufficient to induce IL-2 production upon EpCAM stimulation. An immunofluorescent analysis clearly showed that the CAR57-28ζ induces the formation of signaling clusters containing endogenous CD3ζ at the CAR/EpCAM interaction interface. These results suggest that this CAR gene may be safely and effectively applied for adaptive T-cell immunotherapy.

Use of adoptive transfer of T-cell antigen-receptor-transgenic T cells for the study of T-cell activation in vivo

1997 ◽  
Vol 156 (1) ◽  
pp. 67-78 ◽  
Author(s):  
Kathryn A. Pape ◽  
Elizabeth R. Kearney ◽  
Alexander Khoruts ◽  
Anna Mondino ◽  
Rebecca Merica ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Antigen Receptor ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

The Interchain Disulfide Linkage of T-Cell Antigen Receptor-α and -β Chains Is a Prerequisite for T-Cell Activation

1998 ◽  
Vol 190 (2) ◽  
pp. 101-111 ◽  
Author(s):  
Zhanguo Li ◽  
Weiping Wu ◽  
Owen Kemp ◽  
Melinda Stephen ◽  
Nicholas Manolios
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Receptor ◽  
T Cell Antigen Receptor ◽  
Disulfide Linkage ◽  
Cell Antigen Receptor ◽  
Cell Antigen

scholarly journals Removal of C-Terminal Src Kinase from the Immune Synapse by a New Binding Protein

2005 ◽  
Vol 25 (6) ◽  
pp. 2227-2241 ◽  
Author(s):  
Souad Rahmouni ◽  
Torkel Vang ◽  
Andres Alonso ◽  
Scott Williams ◽  
Marianne van Stipdonk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
T Cell Antigen Receptor ◽  
Intracellular Location ◽  
Immune Synapse ◽  
Cell Antigen Receptor ◽  
Cell Antigen

ABSTRACT The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells. Engagement of the T-cell antigen receptor results in a removal of Csk from the lipid raft-associated transmembrane protein PAG/Cbp. Instead, Csk becomes associated with an ∼72-kDa tyrosine-phosphorylated protein, which we identify here as G3BP, a phosphoprotein reported to bind the SH3 domain of Ras GTPase-activating protein. G3BP reduced the ability of Csk to phosphorylate Lck at Y505 by decreasing the amount of Csk in lipid rafts. As a consequence, G3BP augmented T-cell activation as measured by interleukin-2 gene activation. Conversely, elimination of endogenous G3BP by RNA interference increased Lck Y505 phosphorylation and reduced TCR signaling. In antigen-specific T cells, endogenous G3BP moved into a intracellular location adjacent to the immune synapse, but deeper inside the cell, upon antigen recognition. Csk colocalization with G3BP occurred in this “parasynaptic” location. We conclude that G3BP is a new player in T-cell-antigen receptor signaling and acts to reduce the amount of Csk in the immune synapse.

Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-γ1 and Itk activity

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3534-3542 ◽  
Author(s):  
Mi-Ae Kang ◽  
Su-Young Yun ◽  
Jonghwa Won
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
Rosmarinic Acid ◽  
Antigen Receptor ◽  
Tcr Signaling ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Rosmarinic acid (RosA) is a hydroxylated compound frequently found in herbal plants and is mostly responsible for anti-inflammatory and antioxidative activity. Previously, we observed that RosA inhibited T-cell antigen receptor (TCR)– induced interleukin 2 (IL-2) expression and subsequent T-cell proliferation in vitro. In this study, we investigated in detail inhibitory mechanism of RosA on TCR signaling, which ultimately activates IL-2 promoter by activating transcription factors, such as nuclear factor of activated T cells (NF-AT) and activating protein-1 (AP-1). Interestingly, RosA inhibited NF-AT activation but not AP-1, suggesting that RosA inhibits Ca2+- dependent signaling pathways only. Signaling events upstream of NF-AT activation, such as the generation of inositol 1,4,5-triphosphate and Ca2+ mobilization, and tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) were strongly inhibited by RosA. Tyrosine phosphorylation of PLC-γ1 is largely dependent on 3 kinds of protein tyrosine kinases (PTKs), ie, Lck, ZAP-70, and Itk. We found that RosA efficiently inhibited TCR-induced tyrosine phosphorylation and subsequent activation of Itk but did not inhibit Lck or ZAP-70. ZAP-70–dependent signaling pathways such as the tyrosine phosphorylation of LAT and SLP-76 and serine/threonine phosphorylation of mitogen-activated protein kinases (MAPKs) were intact in the presence of RosA, confirming that RosA suppresses TCR signaling in a ZAP-70–independent manner. Therefore, we conclude that RosA inhibits TCR signaling leading to Ca2+ mobilization and NF-AT activation by blocking membrane-proximal events, specifically, the tyrosine phosphorylation of inducible T cells kinase (Itk) and PLC-γ1.

Sign in / Sign up

Export Citation Format

Share Document