scholarly journals Actin and agonist MHC–peptide complex–dependent T cell receptor microclusters as scaffolds for signaling

2005 ◽  
Vol 202 (8) ◽  
pp. 1031-1036 ◽  
Author(s):  
Gabriele Campi ◽  
Rajat Varma ◽  
Michael L. Dustin
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Actin Polymerization ◽  
Kinase Inhibitor ◽  
Cell Receptor ◽  
Intercellular Adhesion Molecule ◽  
Cell Contact ◽  
Intercellular Adhesion Molecule 1 ◽  
Planar Bilayers ◽  
Latrunculin A

T cell receptor (TCR) microclusters form within seconds of T cell contact with supported planar bilayers containing intercellular adhesion molecule-1 and agonist major histocompatibility complex (MHC)–peptide complexes, and elevation of cytoplasmic Ca2+ is observed within seconds of the first detectable microclusters. At 0–30 s after contact, TCR microclusters are colocalized with activated forms of Lck, ZAP-70, and the linker for activation of T cells. By 2 min, activated kinases are reduced in the older central microclusters, but are abundant in younger peripheral microclusters. By 5 min, TCR in the central supramolecular activation cluster have reduced activated kinases, whereas faint peripheral TCR microclusters efficiently generated activated Lck and ZAP-70. TCR microcluster formation is resistant to inhibition by Src family kinase inhibitor PP2, but is abrogated by actin polymerization inhibitor latrunculin A. We propose that Src kinase–independent formation of TCR microclusters in response to agonist MHC–peptide provides an actin-dependent scaffold for signal amplification.

scholarly journals Actin polymerization regulates recruitment of Nck to CD3 ε upon T‐cell receptor triggering

Immunology ◽  
2019 ◽  
Vol 159 (3) ◽  
pp. 298-308
Author(s):  
Piyamaporn Wipa ◽  
Pussadee Paensuwan ◽  
Jatuporn Ngoenkam ◽  
Nadine M. Woessner ◽  
Susana Minguet ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Actin Polymerization ◽  
Cell Receptor

scholarly journals Dynamic Actin Polymerization Drives T Cell Receptor–Induced Spreading

Immunity ◽  
2001 ◽  
Vol 14 (3) ◽  
pp. 315-329 ◽  
Author(s):  
Stephen C. Bunnell ◽  
Veena Kapoor ◽  
Ronald P. Trible ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Actin Polymerization ◽  
Cell Receptor

scholarly journals Constitutive Endocytosis and Degradation of the Pre-T Cell Receptor

2002 ◽  
Vol 195 (12) ◽  
pp. 1585-1597 ◽  
Author(s):  
Maddalena Panigada ◽  
Simona Porcellini ◽  
Eliane Barbier ◽  
Sonja Hoeflinger ◽  
Pierre-André Cazenave ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Ubiquitin Ligase ◽  
Actin Polymerization ◽  
Cell Receptor ◽  
Surface Expression ◽  
Dominant Negative ◽  
Thymic Stroma ◽  
Tcr Signals

The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56lck, actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the γδTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR– but not γδTCR-expressing cells. A role of c-Cbl–mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl–deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function.

scholarly journals Biphasic mechanosensitivity of T cell receptor-mediated spreading of lymphocytes

2019 ◽  
Vol 116 (13) ◽  
pp. 5908-5913 ◽  
Author(s):  
Astrid Wahl ◽  
Céline Dinet ◽  
Pierre Dillard ◽  
Aya Nassereddine ◽  
Pierre-Henri Puech ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cellular Response ◽  
Actin Polymerization ◽  
Cell Spreading ◽  
Cell Receptor ◽  
Substrate Stiffness ◽  
Bond Rupture ◽  
Immune Recognition

Mechanosensing by T cells through the T cell receptor (TCR) is at the heart of immune recognition. While the mechanobiology of the TCR at the molecular level is increasingly well documented, its link to cell-scale response is poorly understood. Here we explore T cell spreading response as a function of substrate rigidity and show that remarkably, depending on the surface receptors stimulated, the cellular response may be either biphasic or monotonous. When adhering solely via the TCR complex, T cells respond to environmental stiffness in an unusual fashion, attaining maximal spreading on an optimal substrate stiffness comparable to that of professional antigen-presenting cells. However, in the presence of additional ligands for the integrin LFA-1, this biphasic response is abrogated and the cell spreading increases monotonously with stiffness up to a saturation value. This ligand-specific mechanosensing is effected through an actin-polymerization–dependent mechanism. We construct a mesoscale semianalytical model based on force-dependent bond rupture and show that cell-scale biphasic or monotonous behavior emerges from molecular parameters. As the substrate stiffness is increased, there is a competition between increasing effective stiffness of the bonds, which leads to increased cell spreading and increasing bond breakage, which leads to decreased spreading. We hypothesize that the link between actin and the receptors (TCR or LFA-1), rather than the ligand/receptor linkage, is the site of this mechanosensing.

scholarly journals Target-Cell Contact Activates a Highly Selective Capacitative Calcium Entry Pathway in Cytotoxic T Lymphocytes

2000 ◽  
Vol 148 (3) ◽  
pp. 603-614 ◽  
Author(s):  
Adam Zweifach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Target Cell ◽  
Calcium Influx ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Cell Contact ◽  
Crac Channels

Calcium influx is critical for T cell activation. Evidence has been presented that T cell receptor–stimulated calcium influx in helper T lymphocytes occurs via channels activated as a consequence of depletion of intracellular calcium stores, a mechanism known as capacitative Ca2+ entry (CCE). However, two key questions have not been addressed. First, the mechanism of calcium influx in cytotoxic T cells has not been examined. While the T cell receptor–mediated early signals in helper and cytotoxic T cells are similar, the physiology of the cells is strikingly different, raising the possibility that the mechanism of calcium influx is also different. Second, contact of T cells with antigen-presenting cells or targets involves a host of intercellular interactions in addition to those between antigen–MHC and the T cell receptor. The possibility that calcium influx pathways in addition to those activated via the T cell receptor may be activated by contact with relevant cells has not been addressed. We have used imaging techniques to show that target-cell–stimulated calcium influx in CTLs occurs primarily through CCE. We investigated the permeability of the CTL influx pathway for divalent cations, and compared it to the permeability of CCE in Jurkat human leukemic T cells. CCE in CTLs shows a similar ability to discriminate between calcium, barium, and strontium as CCE in Jurkat human leukemic T lymphocytes, where CCE is likely to mediated by Ca2+ release–activated Ca2+ current (CRAC) channels, suggesting that CRAC channels also underlie CCE in CTLs. These results are the first determination of the mechanism of calcium influx in cytotoxic T cells and the first demonstration that cell contact–mediated calcium signals in T cells occur via depletion-activated channels.

scholarly journals Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex.

1995 ◽  
Vol 181 (5) ◽  
pp. 1881-1886 ◽  
Author(s):  
T Aoe ◽  
Y Okamoto ◽  
T Saito
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Structural Changes ◽  
Cell Receptor ◽  
Cell Contact ◽  
Tumor Bearing ◽  
Zeta Chain ◽  
Normal Expression ◽  
Structural Abnormalities

The mechanism of the structural alterations of the T cell receptor (TCR)-CD3 complex, which appear to be greatly responsible for immunosuppression in the tumor-bearing status, was investigated in tumor-bearing mice. Splenic T cells from tumor-bearing hosts lost the expression of the CD3 zeta chain without being replaced by FcR gamma, despite the normal expression of other components of the TCR complex. Tumor growth induced the accumulation of non-T, non-B cells in the spleen in correlation with the loss of zeta. Those cells were found to be macrophages that were able to induce the loss of zeta, as well as structural changes of CD3 gamma delta epsilon, even in freshly isolated normal T cells by cell contact-dependent interaction. More importantly, macrophages activated with zymosan A+LPS but not residential macrophages were able to induce the similar abnormality of the TCR complex. These results indicate that macrophages in certain activation stages play a crucial role in causing an abnormal TCR complex in tumor-bearing conditions, as well as in regulating the structure of the TCR complex in immune responses.

scholarly journals T-Cell Receptor Activation Initiates Multiple Modes of Actin Polymerization within the Immune Synapse

2012 ◽  
Vol 102 (3) ◽  
pp. 349a
Author(s):  
Erdem Tabdanov ◽  
Alexander Gondarenko ◽  
Ryan Kerslake ◽  
James C. Hone ◽  
Lance C. Kam
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Actin Polymerization ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Multiple Modes ◽  
Immune Synapse

Eradication of B-CLL by autologous and allogeneic host nonreactive anti–third-party CTLs

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3365-3371 ◽  
Author(s):  
Fabian D. Arditti ◽  
Shraga Aviner ◽  
Benjamin Dekel ◽  
Rita Krauthgamer ◽  
Judith Gan ◽  
...  
Keyword(s):  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Third Party ◽  
Host Cells ◽  
Intercellular Adhesion Molecule ◽  
Cell Contact ◽  
Lymphocyte Function ◽  
Intercellular Adhesion Molecule 1 ◽  
Chimeric Model

Abstract Establishment of cell lines capable of killing leukemia cells, in the absence of alloreactivity against normal host cells, represents a most desirable goal in bone marrow transplantation (BMT) and cancer immunotherapy. By using a human → mouse chimeric model, we demonstrate that allogeneic anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity are endowed with a potent anti-B-cell chronic lymphocytic leukemia (B-CLL) reactivity. Likewise, CTL preparations generated from autologous T cells of the same patients with B-CLL exhibited comparable leukemia eradication, suggesting that the reactivity of allogeneic anti-third-party CTLs is not mediated by residual antihost clones. This specificity was also exhibited in vitro, and annexin staining revealed that B-CLL killing is mediated by apoptosis. While the CTLs killing of third-party cells could be blocked by anti-CD3 antibody, the lysis of the B-CLL cells was not inhibited by this antibody, suggesting a T-cell receptor (TCR)-independent cytotoxicity. The role of cell contact leading to apoptosis of B-CLL cells is shown in transwell plates and by anti-lymphocyte function-associated antigen-1 (LFA-1)-blocking antibody. Up-regulation of CD54 and the subsequent apoptosis of B-CLL cells depend on the initial LFA-1/ICAM-1 (intercellular adhesion molecule 1) interaction. Taken together, these results suggest that allogeneic or autologous host nonreactive anti-third-party CTLs may represent a new therapeutic approach for patients with B-CLL. (Blood. 2005;105:3365-3371)

scholarly journals Gene transcription in differentiating immature T cell receptor(neg) thymocytes resembles antigen-activated mature T cells.

1993 ◽  
Vol 178 (4) ◽  
pp. 1139-1149 ◽  
Author(s):  
J C Zúñiga-Pflücker ◽  
H L Schwartz ◽  
M J Lenardo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Intercellular Adhesion Molecule ◽  
Brdu Incorporation ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Activated T Cells ◽  
Heat Stable Antigen

Early in ontogeny thymocytes have a surface marker phenotype that resembles activated mature T cells but they lack expression of the T cell receptor (TCR) complex. We have made preparations of day 14/15 triple negative fetal thymocytes that exhibit the activated T lymphocyte markers CD25, intercellular adhesion molecule 1, Ly-6A/E, CD44, and heat stable antigen and are rapidly proliferating as evidenced by flow cytometric examination of BrdU incorporation. We found that binding activities of the gene regulators nuclear factor (NF)-kappa B, the NF-kappa B p50 homodimer complex, nuclear factor of activated T cells (NF-AT), oct-1, oct-2, activator protein 1 (AP-1), and serum response factor (SRF), are all present in these early thymocytes. Whereas the octamer factors and SRF persist during ontogeny, NF-kappa B, NF-AT, and AP-1 decrease and are undetectable in the adult thymus. Transfection of disaggregated thymocytes by electroporation or intact thymic lobes by gold-particle bombardment revealed that reporter constructs for NF-kappa B, NF-AT, AP-1, octamer factors and, to a small extent, the TCR-alpha enhancer were active in early thymocyte development. We rigorously eliminated the possibility that these transcriptional events were due to minor populations of TCR+ cells by showing that these reporter constructs were also active in recombinase activating gene (RAG)-/- thymocytes that are incapable of completing TCR gene rearrangement, and predominantly contain cells that have an activated phenotype. Thus, transcriptional events that are usually triggered by antigen stimulation in mature T cells take place early in thymic ontogeny in the absence of the TCR. Our analysis suggests that there are striking regulatory similarities but also important differences between the activation processes that take place in antigen-stimulated mature T cells and thymic progenitor cells.

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