scholarly journals Are rafts involved in T-cell receptor signalling? Introduction to the Talking Point on the involvement of lipid rafts in T-cell activation

EMBO Reports ◽  
2008 ◽  
Vol 9 (6) ◽  
pp. 523-524 ◽  
Author(s):  
Ben de Wet ◽  
Thomas Harder
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Signalling

scholarly journals T-Cell Receptor Microclusters Critical for T-Cell Activation Are Formed Independently of Lipid Raft Clustering

2010 ◽  
Vol 30 (14) ◽  
pp. 3421-3429 ◽  
Author(s):  
Akiko Hashimoto-Tane ◽  
Tadashi Yokosuka ◽  
Chitose Ishihara ◽  
Machie Sakuma ◽  
Wakana Kobayashi ◽  
...  
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Lipid Raft ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Resonance Energy ◽  
Careful Analysis ◽  
Cell Receptor

ABSTRACT We studied the function of lipid rafts in generation and signaling of T-cell receptor microclusters (TCR-MCs) and central supramolecular activation clusters (cSMACs) at immunological synapse (IS). It has been suggested that lipid raft accumulation creates a platform for recruitment of signaling molecules upon T-cell activation. However, several lipid raft probes did not accumulate at TCR-MCs or cSMACs even with costimulation and the fluorescence resonance energy transfer (FRET) between TCR or LAT and lipid raft probes was not induced at TCR-MCs under the condition of positive induction of FRET between CD3ζ and ZAP-70. The analysis of LAT mutants revealed that raft association is essential for the membrane localization but dispensable for TCR-MC formation. Careful analysis of the accumulation of raft probes in the cell interface revealed that their accumulation occurred after cSMAC formation, probably due to membrane ruffling and/or endocytosis. These results suggest that lipid rafts control protein translocation to the membrane but are not involved in the clustering of raft-associated molecules and therefore that the lipid rafts do not serve as a platform for T-cell activation.

Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 1002-1010 ◽  
Author(s):  
Seiji Kobayashi ◽  
Kei Ohnuma ◽  
Masahiko Uchiyama ◽  
Kouichi Iino ◽  
Satoshi Iwata ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Cell Protein ◽  
Membrane Microdomains

AbstractCD26 is a T-cell activation antigen that contains dipeptidyl peptidase IV activity and binds adenosine deaminase. Recent work showed that specialized membrane microdomains, also known as lipid rafts, play a key role in T-cell signaling. In this study, we investigate the role of CD26 in cord blood T-cell activation and signal transduction. We demonstrated that different expression levels of CD26 were observed between cord blood T cells (CBTCs) and peripheral blood T cells (PBTCs) and that CD26+CD45RA+ CBTCs were different compared with CD26+CD45RA+ PBTCs. Moreover, the comitogenic effect of CD26 was not as pronounced in CBTCs as in PBTCs. We also showed that CD26 cross-linking induced less phosphorylation of T-cell receptor-signaling molecules, lymphoid T-cell protein tyrosine kinase (Lck), zeta-associated protein 70 (ZAP-70), T-cell receptor ζ (TCRζ), and linker for activator of T cells (LAT) in CBTCs than in PBTCs. Furthermore, CD26 molecules associated with CD45RA molecules outside lipid rafts in CBTCs. Our results suggest that strong physical linkage of CD26 with CD45RA outside lipid rafts may be responsible for the attenuation of T-cell activation signaling through CD26, which may be responsible for immature immune response and the low incidence of severe graft-versus-host disease in cord blood transplantation. (Blood. 2004;103:1002-1010)

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.

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Science ◽  
2021 ◽  
Vol 372 (6546) ◽  
pp. eabe9124
Author(s):  
Pirooz Zareie ◽  
Christopher Szeto ◽  
Carine Farenc ◽  
Sachith D. Gunasinghe ◽  
Elizabeth M. Kolawole ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Signaling ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Direct Consequence ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Cell Repertoire

T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRβ-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

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