scholarly journals Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells

2005 ◽  
Vol 201 (3) ◽  
pp. 419-430 ◽  
Author(s):  
June L. Round ◽  
Tamar Tomassian ◽  
Min Zhang ◽  
Viresh Patel ◽  
Stephen P. Schoenberger ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Polarity ◽  
T Cell Receptor ◽  
Lipid Raft ◽  
Actin Polymerization ◽  
Cell Receptor ◽  
Effector Function ◽  
Cellular Systems ◽  
Cell Junctions ◽  
Cell Synapse

Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck–Dlgh1–Zap70–Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems.

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 Functional Reprogramming of the Primary Immune Response by T Cell Receptor Antagonism

2004 ◽  
Vol 200 (11) ◽  
pp. 1371-1382 ◽  
Author(s):  
Dipica Haribhai ◽  
Brandon Edwards ◽  
Mary L. Williams ◽  
Calvin B. Williams
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effector Function ◽  
Primary Immune Response ◽  
Cell Homing ◽  
T Cell Homing ◽  
Cell Receptor Antagonism

The T cell receptor must translate modest, quantitative differences in ligand binding kinetics into the qualitatively distinct signals used to determine cell fate. Here, we use mice that express an endogenous T cell receptor (TCR) antagonist and an adoptive transfer system to examine the influence of TCR signal quality on the development of effector function. We show that activation of antigen-specific T cells in the presence of an antagonist results in a functional reprogramming of the primary immune response, marked by altered T cell homing, a failure to develop effector function, and ultimately clonal elimination by apoptosis. Importantly, antagonism does not block cell division, implying that the signals promoting clonal expansion and effector differentiation are distinct.

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 Association of Herpesvirus Saimiri Tip with Lipid Raft Is Essential for Downregulation of T-Cell Receptor and CD4 Coreceptor

2006 ◽  
Vol 80 (1) ◽  
pp. 108-118 ◽  
Author(s):  
Nam-Hyuk Cho ◽  
Dior Kingston ◽  
Heesoon Chang ◽  
Eun-Kyung Kwon ◽  
Jo-Min Kim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
Lipid Raft ◽  
Cell Receptor ◽  
Surface Expression ◽  
Herpesvirus Saimiri ◽  
Stat3 Transcription Factor ◽  
Tcr Signal Transduction

ABSTRACT Lipid rafts are membrane microdomains that are proposed to function as platforms for both receptor signaling and trafficking. Our previous studies have demonstrated that Tip of herpesvirus saimiri (HVS), which is a T-lymphotropic tumor virus, is constitutively targeted to lipid rafts and interacts with cellular Lck tyrosine kinase and p80 WD repeat-containing endosomal protein. Through the interactions with Lck and p80, HVS Tip modulates diverse T-cell functions, which leads to the downregulation of T-cell receptor (TCR) and CD4 coreceptor surface expression, the inhibition of TCR signal transduction, and the activation of STAT3 transcription factor. In this study, we investigated the functional significance of Tip association with lipid rafts. We found that Tip expression remarkably increased lipid raft fractions in human T cells by enhancing the recruitment of lipid raft-resident proteins. Genetic analysis showed that the carboxyl-terminal transmembrane, but not p80 and Lck interaction, of Tip was required for the lipid raft localization and that lipid raft localization of Tip was necessary for the efficient downregulation of TCR and CD4 surface expression. Correlated with this, treatment with Filipin III, a lipid raft-disrupting agent, effectively reversed the downregulation of CD3 and CD4 surface expression induced by Tip. On the other hand, Tip mutants that were no longer present in lipid rafts were still capable of inhibiting TCR signaling and activating STAT3 transcription factor activity as efficiently as wild-type (wt) Tip. These results indicate that the association of Tip with lipid rafts is essential for the downregulation of TCR and CD4 surface expression but not for the inhibition of TCR signal transduction and the activation of STAT3 transcription factor. These results also suggest that the signaling and targeting activities of HVS Tip rely on functionally and genetically separable mechanisms, which may independently modulate T-cell function for viral persistence or pathogenesis.

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.

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