scholarly journals Antibody-induced modulation of the CD3/T cell receptor complex causes T cell refractoriness by inhibiting the early metabolic steps involved in T cell activation.

1987 ◽  
Vol 166 (2) ◽  
pp. 619-624 ◽  
Author(s):  
G Pantaleo ◽  
D Olive ◽  
A Poggi ◽  
T Pozzan ◽  
L Moretta ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Complex ◽  
Strong Inhibition ◽  
Receptor Ligand ◽  
Ligand Interactions ◽  
Surface Modulation

We investigated the mechanism involved in T cell unresponsiveness that follows the monoclonal antibody-induced surface modulation of the CD3-TCR complex. We determined whether modulation of CD3-TCR affected the early metabolic steps such as [Ca2+]i rise and InsP3 formation. A strong inhibition of the increase on [Ca2+]i mediated by either anti-TCR or anti-CD2 mAbs was detected. In contrast, surface modulation of CD2 molecules did not prevent the [Ca2+]i increase induced by anti-TCR mAb. Similarly, InsP3 increase was strongly reduced only after modulation of CD3-TCR complex (but not of CD2 molecules). Therefore, it appears that surface modulation of CD3-TCR complex causes T cell refractoriness by inhibiting the very early metabolic events that follow receptor-ligand interactions.

scholarly journals Ultrasmall silica nanoparticles directly ligate the T cell receptor complex

2019 ◽  
Vol 117 (1) ◽  
pp. 285-291 ◽  
Author(s):  
Bradley Vis ◽  
Rachel E. Hewitt ◽  
Tom P. Monie ◽  
Camilla Fairbairn ◽  
Suzanne D. Turner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Silica Nanoparticles ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Orthosilicic Acid ◽  
Receptor Complex ◽  
The Impact

The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex–particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain–associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.

scholarly journals Role of the T Cell Receptor Ligand Affinity in T Cell Activation by Bacterial Superantigens

2001 ◽  
Vol 276 (36) ◽  
pp. 33452-33457 ◽  
Author(s):  
Peter S. Andersen ◽  
Carsten Geisler ◽  
Søren Buus ◽  
Roy A. Mariuzza ◽  
Klaus Karjalainen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Ligand ◽  
Ligand Affinity ◽  
Bacterial Superantigens

Signal transducing mechanisms involved in human T cell activation via surface T44 molecules. Comparison with signals transduced via the T cell receptor complex

1986 ◽  
Vol 16 (12) ◽  
pp. 1639-1642 ◽  
Author(s):  
Giuseppe Pantaleo ◽  
Daniel Olive ◽  
David Harris ◽  
Alessandro Poggi ◽  
Lorenzo Moretta ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Complex ◽  
Human T Cell

scholarly journals T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T).

1993 ◽  
Vol 178 (6) ◽  
pp. 2107-2113 ◽  
Author(s):  
A J da Silva ◽  
O Janssen ◽  
C E Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
T Complex

Intracellular signaling from the T cell receptor (TCR)zeta/CD3 complex is likely to be mediated by associated protein tyrosine kinases such as p59fyn(T), ZAP-70, and the CD4:p56lck and CD8:p56lck coreceptors. The nature of the signaling cascade initiated by these kinases, their specificities, and downstream targets remain to be elucidated. The TCR-zeta/CD3:p59fyn(T) complex has previously been noted to coprecipitate a 120/130-kD doublet (p120/130). This intracellular protein of unknown identity associates directly with p59fyn(T) within the receptor complex. In this study, we have shown that this interaction with p120/130 is specifically mediated by the SH2 domain (not the fyn-SH3 domain) of p59fyn(T). Further, based on the results of in vitro kinase assays, p120/130 appears to be preferentially associated with p59fyn(T) in T cells, and not with p56lck. Antibody reprecipitation studies identified p120/130 as a previously described 130-kD substrate of pp60v-src whose function and structure is unknown. TCR-zeta/CD3 induced activation of T cells augmented the tyrosine phosphorylation of p120/130 in vivo as detected by antibody and GST:fyn-SH2 fusion proteins. p120/130 represents the first identified p59fyn(T):SH2 binding substrate in T cells, and as such is likely to play a key role in the early events of T cell activation.

scholarly journals A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex

2020 ◽  
Author(s):  
Lina Freage ◽  
Deana Jamal ◽  
Nicole Williams ◽  
Prabodhika R. Mallikaratchy
Keyword(s):  
T Cell ◽  
Nucleic Acid ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Cluster ◽  
Pharmacokinetic Properties ◽  
Activation Potential ◽  
Cluster Of Differentiation

AbstractRecently, immunotherapeutic modalities with engineered cells and monoclonal antibodies have been effective in treating several malignancies. However, growing evidence suggests that immune-related adverse events (irAE) lead to severe and long-term side effects. Most iRAEs involve prolonged circulation of antibodies. To address this problem, nucleic acid aptamers can serve as alternative molecules to design immunotherapeutics with high functional diversity and predictable circulation times. Here, we report the first synthetic prototype consisting of DNA aptamers, which can activate T-cell receptor cluster of differentiation 3 (TCR-CD3) complex in cultured T-cells. We show that activation potential is similar to that of a monoclonal antibody (mAb) against TCR-CD3, suggesting the potential of aptamers in developing efficacious synthetic immunomodulators. The synthetic prototype of anti-TCR-CD3ε, as described herein, was designed using aptamer ZUCH-1 against TCR-CD3ε, generated by Ligand Guided Selection (LIGS). Aptamer ZUCH-1 was truncated and modified with nuclease-resistant RNA analogs to enhance stability. Several dimeric analogs with truncated and modified variants were designed with variable linker lengths to investigate the activation potential of each construct. Among them, dimeric aptamer with approximate dimensions similar to those of an antibody showed the highest T-cell-activation, suggesting the importance of optimizing linker lengths in engineering functional aptamers. The observed activation potential of dimeric aptamers shows the vast potential of aptamers in designing synthetically versatile immunomodulators with tunable pharmacokinetic properties, expanding immunotherapeutic designs with the use of nucleic acid-based ligands such as aptamers.

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