scholarly journals T Cell Membrane Heterogeneity Aids Antigen Recognition and T Cell Activation

2020 ◽  
Vol 8 ◽  
Author(s):  
Megan V. Farrell ◽  
Samantha Webster ◽  
Katharina Gaus ◽  
Jesse Goyette
Keyword(s):  
T Cell ◽  
Cell Membrane ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Recognition ◽  
Membrane Heterogeneity ◽  
T Cell Membrane

scholarly journals The interplay between membrane topology and mechanical forces in regulating T cell receptor activity

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Mohammad Ameen Al-Aghbar ◽  
Ashwin K. Jainarayanan ◽  
Michael L. Dustin ◽  
Steve R. Roffler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Membrane ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Membrane Topology ◽  
Mechanical Forces ◽  
T Cell Membrane

AbstractT cells are critically important for host defense against infections. T cell activation is specific because signal initiation requires T cell receptor (TCR) recognition of foreign antigen peptides presented by major histocompatibility complexes (pMHC) on antigen presenting cells (APCs). Recent advances reveal that the TCR acts as a mechanoreceptor, but it remains unclear how pMHC/TCR engagement generates mechanical forces that are converted to intracellular signals. Here we propose a TCR Bending Mechanosignal (TBM) model, in which local bending of the T cell membrane on the nanometer scale allows sustained contact of relatively small pMHC/TCR complexes interspersed among large surface receptors and adhesion molecules on the opposing surfaces of T cells and APCs. Localized T cell membrane bending is suggested to increase accessibility of TCR signaling domains to phosphorylation, facilitate selective recognition of agonists that form catch bonds, and reduce noise signals associated with slip bonds.

scholarly journals TAP, a novel T cell-activating protein involved in the stimulation of MHC-restricted T lymphocytes.

1986 ◽  
Vol 163 (2) ◽  
pp. 315-333 ◽  
Author(s):  
K L Rock ◽  
E T Yeh ◽  
C F Gramm ◽  
S I Haber ◽  
H Reiser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Membrane ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Accessory Cells ◽  
T Cell Membrane ◽  
Stimulation Of

Five mAbs have been generated and used to characterize TAP (T cell activating protein) a novel, functional murine T cell membrane antigen. The TAP molecule is a 12-kD protein that is synthesized by T cells. By antibody crossblocking, it appears to be closely associated with a 16-kD protein on the T cell membrane also identified with a novel mAb. These molecules are clearly distinct from the major well-characterized murine T cell antigens previously described. Antibody binding to TAP can result in the activation of MHC-restricted, antigen-specific inducer T cell hybridomas that is equivalent in magnitude to maximal antigen or lectin stimulation. This is a direct effect of soluble antibody and does not require accessory cells or other factors. The activating anti-TAP mAbs are also mitogenic for normal heterogeneous T lymphocytes in the presence of accessory cells or IL-1. In addition, these antibodies are observed to modulate specific immune stimulation. Thus, the activating anti-TAP mAbs synergise with antigen-specific stimulation of T cells, while a nonactivating anti-TAP mAb inhibits antigen driven activation. These observations suggest that the TAP molecule may participate in physiologic T cell activation. The possible relationship of TAP to known physiologic triggering structures, the T3-T cell receptor complex, is considered. TAP is expressed on 70% of peripheral T cells and therefore defines a major T cell subset, making it perhaps the first example of a murine subset-specific activating protein.

scholarly journals PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kaitao Li ◽  
Zhou Yuan ◽  
Jintian Lyu ◽  
Eunseon Ahn ◽  
Simon J. Davis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Success ◽  
Clinical Intervention ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Antigen Recognition ◽  
Inhibitory Function ◽  
Src Homology

AbstractDespite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1’s targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR–pMHC–CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1’s potent inhibitory function and its value as a target for clinical intervention.

scholarly journals A new HLA-linked T cell membrane molecule, related to the beta chain of the clonotypic receptor, is associated with T3.

1986 ◽  
Vol 164 (2) ◽  
pp. 458-473 ◽  
Author(s):  
Y Bushkin ◽  
D N Posnett ◽  
B Pernis ◽  
C Y Wang
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Functional Role ◽  
Cell Activation ◽  
Cell Receptor ◽  
Leukemia Cells ◽  
Alpha Beta ◽  
Beta 2 Microglobulin ◽  
T Cell Membrane ◽  
Membrane Molecule

The 38 kD molecule is noncovalently associated with beta 2 microglobulin (beta 2m)-free HLA heavy chain-like molecule, and thus forms a second heterodimer distinct from the clonotypic alpha/beta T cell receptor expressed by the same clone of leukemia cells. This second heterodimer (38 kD/HLA) is variably expressed and appears to be associated with the T3 molecule. We suggest, therefore, that it has a functional role in T cell activation.

scholarly journals Development of Acute Myeloid Leukemia Cell Membrane Coated Nanoparticles (AMCNPs) for Cancer Vaccination Immunotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4062-4062
Author(s):  
Daniel T Johnson ◽  
Ashley V Kroll ◽  
Ronnie H Fang ◽  
Justin Kline ◽  
Liangfang Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Membrane ◽  
Immune Responses ◽  
Mhc Class I ◽  
T Cell Activation ◽  
Cell Activation ◽  
Residual Disease ◽  
Surface Antigens ◽  
Class I

Abstract Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults and has a five-year survival rate under 50%. Most patients will relapse even after complete remission is achieved through standard chemotherapy. Thus, one barrier in current AML therapy is how to target the minimal residual disease during remission. Recent developments in understanding cancer cell antigen presentation and immunosuppression have revealed the promise of cancer immunotherapy in activating immune responses to target residual disease. Each leukemia patient has a unique spectrum of cell surface antigens, which are mostly uncharacterized. If these antigens can be efficiently presented to the patient's immune system, immune responses to fight the leukemia can be significantly enhanced. We therefore sought to develop and characterize an AML cell membrane-coated nanoparticle (AMCNP) platform with nanoparticles (NPs) carrying the same surface antigens as the source leukemic cells for use as an anti-cancer vaccine. To demonstrate that our AMCNP vaccines enhance leukemia-specific antigen dendritic cell (DC) presentation and T-cell responses, we modified the C1498 murine AML cell line to express membrane-bound chicken ovalbumin (C1498-mOVA) as a model antigen. We confirmed that the C1498-mOVA line presents the OVA MHC class-I "SIINFEKL" antigen through flow-cytometry and LacZ B3Z T-cell activation assays. The C1498-mOVA line remained leukemogenic when injected into C57BL/6 mice, with survival times between 30 and 55 days. We generated both C1498 and C1498-mOVA membrane-coated nanoparticles, that were packaged with CpG oligo-deoxynucleotides (CpG) as an immune-stimulatory adjuvant. The final AMCNPs exhibit a core-shell structure with uniform coating as shown by transmission electron microscopy. The C1498-mOVA AMCNPs retained mOVA antigen. To confirm that the C1498-mOVA AMCNPs can effectively stimulate DC OVA MHC class I cross-presentation, we pulsed primary bone marrow derived DCs with C1498 AMCNPs or C1498-mOVA AMCNPs; only the C1498-mOVA AMCNP pulsed DCs specifically elicited OVA MHC class-I T-cell activation in lacZ B3Z T-cell activation assays. To verify that the AMCNPs can elicit antigen-specific immune responses in vivo, we vaccinated C57BL/6 mice with C1498 AMCNPs, C1498-mOVA AMCNPs, or equivalent amounts of whole cell lysates. When stimulated ex vivo with OVA peptide, immune-cell preparations from the C1498-mOVA AMCNP vaccinated mice showed significantly enhanced production of OVA-specific T-cells and IFN-γ, demonstrating increased immune responses. To assess if the enhanced cellular immunity afforded by the C1498-mOVA AMCNP formula can translate into functional rejection of leukemia cells, we performed a prophylactic study using the C1498-mOVA model. Mice vaccinated with the C1498-mOVA AMCNPs all survived beyond 120 days post C1498-mOVA cell challenge, compared to mock treated control mice which had a median survival of 60 days. Collectively, we developed an AMCNP platform that carries AML surface antigens and can be packaged with immunostimulatory adjuvants. These AMCNPs retained AML specific antigens, elicited enhanced antigen specific immune responses after in vivo vaccination, and improved immunity against AML challenge. Therefore, using AML cell membrane coated NPs to enhance anticancer immunity is a feasible strategy for AML vaccination immunotherapy. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding.

scholarly journals Temporal Analysis of T-Cell Receptor-Imposed Forces via Quantitative Single Molecule FRET Measurements

2020 ◽  
Author(s):  
Janett Göhring ◽  
Florian Kellner ◽  
Lukas Schrangl ◽  
René Platzer ◽  
Enrico Klotzsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lipid Bilayers ◽  
T Cell Activation ◽  
Single Molecule ◽  
Cell Activation ◽  
Antibody Fragment ◽  
Antigen Recognition ◽  
Single Chain ◽  
Single Chain Antibody

ABSTRACTMechanical forces acting on ligand-engaged T-cell receptors (TCRs) have previously been implicated in T-cell antigen recognition, yet their magnitude, spread, and temporal behavior are still poorly defined. We here report a FRET-based sensor equipped with a TCR-reactive single chain antibody fragment, which was tethered to planar supported lipid bilayers (SLBs) and informs most directly on the magnitude and kinetics of TCR-imposed forces at the single molecule level. When confronting T-cells with gel-phase SLBs we observed both prior and upon T-cell activation a single, well-resolvable force-peak of approximately 5 pN and force loading rates on the TCR of 1.5 pN per second. When facing fluid SLBs instead, T-cells still exerted tensile forces yet with threefold reduced magnitude and only prior to but not upon activation. Our findings do not only provide first truly molecular information on TCR-imposed forces within the immunological synapse, they also recalibrate their significance in antigen recognition.

Cell Membrane Molecule I-J Transduces a Negative Signal for Early T-cell Activation Induced via the TCR

1989 ◽  
Vol 54 (0) ◽  
pp. 683-688 ◽  
Author(s):  
Y. Asano ◽  
T. Nakayama ◽  
H. Kishimoto ◽  
T. Komuro ◽  
K. Sano ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Membrane ◽  
T Cell Activation ◽  
Cell Activation ◽  
Membrane Molecule ◽  
Negative Signal

scholarly journals Functionalized bead assay to measure 3-dimensional traction forces during T-cell activation

2020 ◽  
Author(s):  
Morteza Aramesh ◽  
Simon Mergenthal ◽  
Marcel Issler ◽  
Birgit Plochberger ◽  
Florian Weber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Traction Force ◽  
Antigen Recognition ◽  
Traction Force Microscopy ◽  
Superresolution Microscopy ◽  
Force Microscopy ◽  
Antigen Presenting

AbstractWhen T-cells probe their environment for antigens, the bond between the T-cell receptor (TCR) and the peptide-loaded major histocompatibility complex (MHC) is put under tension, thereby influencing the antigen discrimination process. Yet, the quantification of such forces in the context of T-cell signaling is technically challenging. Common approaches such as traction force microscopy (TFM) employ a global readout of the force fields, e.g. by measuring the displacements of hydrogel-embedded marker beads. Recent data, however, indicated that T-cells exert tensile forces locally via TCR-enriched microvilli while scanning the surface of antigen-presenting cells. Here, we developed a traction force microscopy platform, which allows for quantifying the pulls exerted via T-cell microvilli, in both tangential and normal directions, during T-cell activation. For this, we immobilized specific T-cell activating antibodies directly on the marker beads used to read out the hydrogel deformation. Microvilli targeted the functionalized beads, as confirmed by superresolution microscopy of the local actin organization. Moreover, we found that cellular components, such as actin, TCR and CD45 reorganize upon interaction with the beads, such that actin forms a vortex-like ring structure around the beads and TCR is enriched at the bead surface, whereas, CD45 is excluded from bead-microvilli contacts.Significance statementDuring the antigen recognition process, T-cells explore and probe their environment via microvilli, which exert local pushes and pulls at the surface of the antigen presenting cell. It is currently believed that these forces influence or even enable the antigen recognition process. Here, we describe the development of a platform, which allows us to quantify the magnitude and direction of traction forces exerted locally by T cell microvilli. Simultaneous Ca2+ imaging was used to link the measured forces to the overall T cell activation status. Superresolution microscopy resolved the contact sites of bead-microvilli contact at the nanoscale: cells contacted beads via actin vortex-like structures, which excluded the phosphatase CD45 from the contacts.

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