scholarly journals Searching for immunotherapeutic targets in oncology during immune synapse formation

2021 ◽  
Vol 67 (3) ◽  
pp. 344-349
Author(s):  
Tatiana Nehaeva ◽  
Artem Karpov ◽  
Nino Pipia
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Ligand Molecule ◽  
Receptor Ligands ◽  
Immune Synapse ◽  
Central Cluster ◽  
Antigen Presenting

Immunological synapse (IS) is a high-specialized connection between a T-lymphocyte and an antigen-presenting cell (APC), consisting of a cluster of T-cell receptors (TCR) surrounded by a ring of adhesion molecules. It has now been shown that formation of immune synapses is an active and dynamic mechanism that allows T cells to discriminate between potential antigenic ligands. At the first stage T-cell receptor ligands are involved in the external ring of the forming synapse. The movement of these complexes into the central cluster depends on the kinetics of T-cell receptor-ligand molecule interaction. Thus, the formation of a stable central cluster in the immunological synapse is a determining event for T-cell proliferation. The application of effective ways to influence on the IS by introduction into practice of new antitumor drugs and immunological synapse modulators allows to take a new look at the possibilities of tumor immunotherapy.

scholarly journals Agent-Based Modeling of T Cell Receptor Cooperativity

2020 ◽  
Vol 21 (18) ◽  
pp. 6473
Author(s):  
Anastasios Siokis ◽  
Philippe A. Robert ◽  
Michael Meyer-Hermann
Keyword(s):  
T Cell ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Agent Based Model ◽  
Tcr Signaling ◽  
Immune Synapse ◽  
Agent Based ◽  
Affinity Modulation ◽  
Antigen Peptide

Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR–pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon.

scholarly journals Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse

2016 ◽  
Vol 215 (3) ◽  
pp. 383-399 ◽  
Author(s):  
Sricharan Murugesan ◽  
Jinsung Hong ◽  
Jason Yi ◽  
Dong Li ◽  
Jordan R. Beach ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Immunological Synapse ◽  
Three Dimensional ◽  
Cell Receptor ◽  
Structured Illumination ◽  
Structured Illumination Microscopy ◽  
Tcr Signaling ◽  
Immune Synapse ◽  
Distal Edge

Actin assembly and inward flow in the plane of the immunological synapse (IS) drives the centralization of T cell receptor microclusters (TCR MCs) and the integrin leukocyte functional antigen 1 (LFA-1). Using structured-illumination microscopy (SIM), we show that actin arcs populating the medial, lamella-like region of the IS arise from linear actin filaments generated by one or more formins present at the IS distal edge. After traversing the outer, Arp2/3-generated, lamellipodia-like region of the IS, these linear filaments are organized by myosin II into antiparallel concentric arcs. Three-dimensional SIM shows that active LFA-1 often aligns with arcs, whereas TCR MCs commonly reside between arcs, and total internal reflection fluorescence SIM shows TCR MCs being swept inward by arcs. Consistently, disrupting actin arc formation via formin inhibition results in less centralized TCR MCs, missegregated integrin clusters, decreased T–B cell adhesion, and diminished TCR signaling. Together, our results define the origin, organization, and functional significance of a major actomyosin contractile structure at the IS that directly propels TCR MC transport.

scholarly journals The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation

2020 ◽  
Vol 21 (8) ◽  
pp. 2859
Author(s):  
Sara G. Dosil ◽  
Amelia Rojas-Gomez ◽  
Francisco Sánchez-Madrid ◽  
Noa B. Martín-Cófreces
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Cell Receptor ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Immune Synapse ◽  
Antigen Presenting

The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.

scholarly journals Agent-Based Modeling of T Cell Receptor Cooperativity

2020 ◽  
Author(s):  
Anastasios Siokis ◽  
Philippe A. Robert ◽  
Michael Meyer-Hermann
Keyword(s):  
T Cell ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Agent Based Model ◽  
Tcr Signaling ◽  
Immune Synapse ◽  
Agent Based ◽  
Affinity Modulation ◽  
Antigen Peptide

AbstractImmunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time, and depends on the density of ligand pMHC (antigen peptide presented by major histocompatibility complexes) and TCR molecules. Comparison between the presence or absence of TCR-pMHC centrally directed flow due to F-actin coupling suggest centripetal transport is a potential mechanism for the affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model, shows that TCR affinity can potentially be actively modulated by a positive/negative feedback of F-actin foci on the TCR-pMHC association rate kon.

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