scholarly journals Stochastic model of T Cell repolarization during target elimination (I)

2019 ◽  
Author(s):  
I. Hornak ◽  
H. Rieger
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Immunological Synapse ◽  
Molecular Motor ◽  
Cell Polarization ◽  
Target Cells ◽  
Microtubule Organizing Center ◽  
Tight Contact ◽  
Sliding Mechanism ◽  
Spatio Temporal

AbstractCytotoxic T lymphocytes (T) and natural killer (NK) cells are the main cytotoxic killer cells of the human body to eliminate pathogen-infected or tumorigenic cells (i.e. target cells). Once a NK or T cell has identified a target cell, they form a tight contact zone, the immunological synapse (IS). One then observes a re-polarization of the cell involving the rotation of the microtubule (MT) half-spindle and a movement of the microtubule organizing center (MTOC) to a position that is just underneath the plasma membrane at the center of the IS. Concomitantly a massive relocation of organelles attached to MTs is observed, including the Golgi apparatus, lytic granules and mitochondria. Since the mechanism of this relocation is still elusive we devise a theoretical model for the molecular motor driven motion of the MT half-spindle confined between plasma membrane and nucleus during T cell polarization. We analyze different scenarios currently discussed in the literature, the cortical sliding and the capture-shrinkage mechanisms, and compare quantitative predictions about the spatio-temporal evolution of MTOC position and spindle morphology with experimental observations. The model predicts the experimentally observed biphasic nature of the repositioning process due to an interplay between spindle geometry and motor forces and confirms the dominance of the capture-shrinkage over the cortical sliding mechanism when MTOC and IS are initially diametrically opposed. We also find that the two mechanisms act synergetically, thereby reducing the resources necessary for repositioning. Moreover, it turns out that the localization of dyneins in the pSMAC facilitates their interaction with the MTs. Our model also opens a way to infer details of the dynein distribution from the experimentally observed features of the MT half-spindle dynamics. In a subsequent publication we will address the issue of general initial configurations and situations in which the T cell established two immunological synapses.

scholarly journals Stochastic model of T Cell repolarization during target elimination (II)

2021 ◽  
Author(s):  
Ivan Hornak ◽  
Heiko Rieger
Keyword(s):  
T Cell ◽  
Immunological Synapse ◽  
Molecular Motor ◽  
Initial Position ◽  
Cell Polarization ◽  
Target Cells ◽  
Microtubule Organizing Center ◽  
Tight Contact ◽  
Organizing Center ◽  
Arbitrary Position

Cytotoxic T lymphocytes (T cells) and natural killer cells form a tight contact, the immunological synapse (IS), with target cells, where they release their lytic granules containing perforin/granzyme and cytokine containing vesicles. During this process the cell repolarizes and moves the microtubule organizing center (MTOC) towards the IS. In the first part of our work we developed a computational model for the molecular-motor-driven motion of the MT cytoskeleton confined between plasma membrane and nucleus during T cell polarization and analyzed different mechanisms (cortical sliding and capture-shrinkage) that have been proposed on the basis of recent experiments. Here we use this model to analyze the dynamics of the MTOC during the repositioning process in situations in which a) the IS is in an arbitrary position with respect to the initial position of the MTOC and b) the T cell has two IS at two arbitrary positions. We observe several scenarios that have also been reported experimentally: the MTOC alternates stochastically (but with a well defined average transition time) between the two IS; it wiggles in between the two IS without transiting to one of the two; or it is at some point pulled to one of the two IS and stays there. Our model allows to predict which scenario emerges in dependency of the mechanisms in action and the number of dyneins present.

scholarly journals Centrosome docking at the immunological synapse is controlled by Lck signaling

2011 ◽  
Vol 192 (4) ◽  
pp. 663-674 ◽  
Author(s):  
Andy Tsun ◽  
Ihjaaz Qureshi ◽  
Jane C. Stinchcombe ◽  
Misty R. Jenkins ◽  
Maike de la Roche ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Cytotoxic T Lymphocytes ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Target Cells ◽  
Lytic Granules ◽  
Distal Side

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor–activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane.

scholarly journals An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes

2008 ◽  
Vol 205 (13) ◽  
pp. 3201-3213 ◽  
Author(s):  
Olga Antón ◽  
Alicia Batista ◽  
Jaime Millán ◽  
Laura Andrés-Delgado ◽  
Rosa Puertollano ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Microtubule Organizing Center ◽  
Transport Pathway ◽  
Specific Transport ◽  
Transport Vesicles ◽  
Organizing Center

The MAL protein is an essential component of the specialized machinery for apical targeting in epithelial cells. The src family kinase Lck plays a pivotal role in T cell signaling. We show that MAL is required in T cells for efficient expression of Lck at the plasma membrane and activation of IL-2 transcription. To investigate the mechanism by which MAL regulates Lck targeting, we analyzed the dynamics of Lck and found that it travels to the plasma membrane in specific transport carriers containing MAL. Coimmunoprecipitation experiments indicated an association of MAL with Lck. Both carrier formation and partitioning of Lck into detergent-insoluble membranes were ablated in the absence of MAL. Polarization of T cell receptor for antigen (TCR) and microtubule-organizing center to immunological synapse (IS) were also defective. Although partial correction of the latter defects was possible by forced expression of Lck at the plasma membrane, their complete correction, formation of transport vesicles, partitioning of Lck, and restoration of signaling pathways, which are required for IL-2 transcription up-regulation, were achieved by exogenous expression of MAL. We concluded that MAL is required for recruitment of Lck to specialized membranes and formation of specific transport carriers for Lck targeting. This novel transport pathway is crucial for TCR-mediated signaling and IS assembly.

scholarly journals Spatiotemporal Regulation of Signaling: Focus on T Cell Activation and the Immunological Synapse

2020 ◽  
Vol 21 (9) ◽  
pp. 3283
Author(s):  
Esther Garcia ◽  
Shehab Ismail
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Signaling Network ◽  
Spatiotemporal Regulation

In a signaling network, not only the functions of molecules are important but when (temporal) and where (spatial) those functions are exerted and orchestrated is what defines the signaling output. To temporally and spatially modulate signaling events, cells generate specialized functional domains with variable lifetime and size that concentrate signaling molecules, enhancing their transduction potential. The plasma membrane is a key in this regulation, as it constitutes a primary signaling hub that integrates signals within and across the membrane. Here, we examine some of the mechanisms that cells exhibit to spatiotemporally regulate signal transduction, focusing on the early events of T cell activation from triggering of T cell receptor to formation and maturation of the immunological synapse.

scholarly journals Lipid order and charge protect killer T cells from accidental death

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jesse A. Rudd-Schmidt ◽  
Adrian W. Hodel ◽  
Tahereh Noori ◽  
Jamie A. Lopez ◽  
Hyun-Jung Cho ◽  
...  
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
Target Cell ◽  
Serine Proteases ◽  
Immunological Synapse ◽  
Synaptic Cleft ◽  
Target Cells ◽  
Lipid Order ◽  
Target Cell Membrane ◽  
Killer T Cells

AbstractKiller T cells (cytotoxic T lymphocytes, CTLs) maintain immune homoeostasis by eliminating virus-infected and cancerous cells. CTLs achieve this by forming an immunological synapse with their targets and secreting a pore-forming protein (perforin) and pro-apoptotic serine proteases (granzymes) into the synaptic cleft. Although the CTL and the target cell are both exposed to perforin within the synapse, only the target cell membrane is disrupted, while the CTL is invariably spared. How CTLs escape unscathed remains a mystery. Here, we report that CTLs achieve this via two protective properties of their plasma membrane within the synapse: high lipid order repels perforin and, in addition, exposed phosphatidylserine sequesters and inactivates perforin. The resulting resistance of CTLs to perforin explains their ability to kill target cells in rapid succession and to survive these encounters. Furthermore, these mechanisms imply an unsuspected role for plasma membrane organization in protecting cells from immune attack.

scholarly journals Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Peter Jan Hooikaas ◽  
Hugo GJ Damstra ◽  
Oane J Gros ◽  
Wilhelmina E van Riel ◽  
Maud Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Polarization ◽  
Contact Site ◽  
Cell Form ◽  
Pulling Forces ◽  
T Cell Polarization ◽  
Microtubule Growth ◽  
Antigen Presenting

When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

scholarly journals Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules

2018 ◽  
Vol 115 (40) ◽  
pp. E9353-E9361 ◽  
Author(s):  
F. Tudor Ilca ◽  
Andreas Neerincx ◽  
Mark R. Wills ◽  
Maike de la Roche ◽  
Louise H. Boyle
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Cell Surface ◽  
Cell Receptor ◽  
Target Cells ◽  
Intact Cells ◽  
Mhc I ◽  
Immunogenic Peptides ◽  
Presentation Pathway ◽  
Peptide Exchange

The repertoire of peptides displayed at the cell surface by MHC I molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-γ secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future.

scholarly journals Cytoskeletal Polarization of T Cells Is Regulated by an Immunoreceptor Tyrosine-based Activation Motif–dependent Mechanism

1998 ◽  
Vol 140 (4) ◽  
pp. 861-871 ◽  
Author(s):  
Bente Lowin-Kropf ◽  
Virginia Smith Shapiro ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Polymerization ◽  
Gene Activation ◽  
Attachment Site ◽  
Cell Polarization ◽  
Cell Contact ◽  
Microtubule Organizing Center ◽  
T Cell Polarization ◽  
Cytoskeletal Rearrangements

Abstract. Binding of a T cell to an appropriate antigen-presenting cell (APC) induces the rapid reorientation of the T cell cytoskeleton and secretory apparatus towards the cell–cell contact site in a T cell antigen receptor (TCR) and peptide/major histocompatibility complex–dependent process. Such T cell polarization directs the delivery of cytokines and cytotoxic mediators towards the APC and contributes to the highly selective and specific action of effector T cells. To study the signaling pathways that regulate cytoskeletal rearrangements in T lymphocytes, we set up a conjugate formation assay using Jurkat T cells as effectors and cell-sized latex beads coated with various antibodies as artificial APCs. Here, we report that beads coated with antibodies specific for the TCR-CD3 complex were sufficient to induce T cell polarization towards the bead attachment site, as judged by reorientation of the microtubule-organizing center (MTOC) and localized actin polymerization. Thus, these cytoskeletal changes did not depend on activation of additional coreceptors. Moreover, single subunits of the TCR complex, namely TCR-ζ and CD3ε, were equally effective in inducing cytoskeletal polarization. However, mutagenesis of the immunoreceptor tyrosine-based activation motifs (ITAMs), present three times in TCR-ζ and once in CD3ε, revealed that the induction of cytoskeletal rearrangements required the presence of at least one intact ITAM. In agreement with this result, lack of functional Lck, the protein tyrosine kinase responsible for ITAM phosphorylation, abolished both MTOC reorientation and polarized actin polymerization. Both inhibitor and transient overexpression studies demonstrated that MTOC reorientation could occur in the absence of Ras activation. Our results suggest that APC-induced T cell polarization is a TCR-mediated event that is coupled to the TCR by the same signaling motif as TCR-induced gene activation, but diverges in its distal signaling requirements.

scholarly journals Mitochondrial and Plasma Membrane Pools of Stomatin-Like Protein 2 Coalesce at the Immunological Synapse during T Cell Activation

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37144 ◽  
Author(s):  
Darah A. Christie ◽  
Mark G. Kirchhof ◽  
Santosh Vardhana ◽  
Michael L. Dustin ◽  
Joaquín Madrenas
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse
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