scholarly journals Degradation of  T Cell Receptor (TCR)–CD3-ζ Complexes after Antigenic Stimulation

1997 ◽  
Vol 185 (10) ◽  
pp. 1859-1864 ◽  
Author(s):  
Salvatore Valitutti ◽  
Sabina Müller ◽  
Mariolina Salio ◽  
Antonio Lanzavecchia
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Time Course ◽  
Cell Activation ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Bafilomycin A1 ◽  
Dose Dependent Decrease ◽  
Antigen Presenting ◽  
Dose Dependent

T cell activation by specific antigen results in a rapid and long-lasting downregulation of triggered T cell receptors (TCRs). In this work, we investigated the fate of downregulated TCR– CD3-ζ complexes. T cells stimulated by peptide-pulsed antigen-presenting cells (APCs) undergo an antigen dose-dependent decrease of the total cellular content of TCR-β, CD3-ε, and ζ chains, as detected by FACS® analysis on fixed and permeabilized T–APC conjugates and by Western blot analysis on cell lysates. The time course of CD3-ζ chain consumption overlaps with that of TCR downregulation, indicating that internalized TCR–CD3 complexes are promptly degraded. Inhibitors of lysosomal function (bafilomycin A1, folimycin) markedly reduced ζ chain degradation, leading to the accumulation of ζ chain in large Lamp1+ vesicles. These results indicate that in T cell–APC conjugates, triggered TCRs are rapidly removed from the cell surface and are degraded in the lysosomal compartment.

scholarly journals Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

2017 ◽  
Vol 114 (46) ◽  
pp. 12190-12195 ◽  
Author(s):  
Rafal M. Pielak ◽  
Geoff P. O’Donoghue ◽  
Jenny J. Lin ◽  
Katherine N. Alfieri ◽  
Nicole C. Fay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Single Molecule ◽  
Cell Activation ◽  
Cell Receptor ◽  
Physical Constraints ◽  
Molecular Binding ◽  
Antigen Presenting

Antigen discrimination by T cells occurs at the junction between a T cell and an antigen-presenting cell. Juxtacrine binding between numerous adhesion, signaling, and costimulatory molecules defines both the topographical and lateral geometry of this cell–cell interface, within which T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) interact. These physical constraints on receptor and ligand movement have significant potential to modulate their molecular binding properties. Here, we monitor individual ligand:receptor binding and unbinding events in space and time by single-molecule imaging in live primary T cells for a range of different pMHC ligands and surface densities. Direct observations of pMHC:TCR and CD80:CD28 binding events reveal that the in situ affinity of both pMHC and CD80 ligands for their respective receptors is modulated by the steady-state number of agonist pMHC:TCR interactions experienced by the cell. By resolving every single pMHC:TCR interaction it is evident that this cooperativity is accomplished by increasing the kinetic on-rate without altering the off-rate and has a component that is not spatially localized. Furthermore, positive cooperativity is observed under conditions where the T cell activation probability is low. This TCR-mediated feedback is a global effect on the intercellular junction. It is triggered by the first few individual pMHC:TCR binding events and effectively increases the efficiency of TCR scanning for antigen before the T cell is committed to activation.

scholarly journals T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state

2007 ◽  
Vol 204 (11) ◽  
pp. 2747-2757 ◽  
Author(s):  
Pia P. Yachi ◽  
Carina Lotz ◽  
Jeanette Ampudia ◽  
Nicholas R.J. Gascoigne
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Endogenous Peptides ◽  
Foreign Peptide ◽  
Antigen Presenting

T cells are extremely sensitive in their ability to find minute amounts of antigenic peptide in the midst of many endogenous peptides presented on an antigen-presenting cell. The role of endogenous peptides in the recognition of foreign peptide and hence in T cell activation has remained controversial for CD8+ T cell activation. We showed previously that in a CD8+ T cell hybridoma, nonstimulatory endogenous peptides enhance T cell sensitivity to antigen by increasing the coreceptor function of CD8. However, others were not able to detect such enhancement in naive and activated CD8+ T cells. Here, we show that endogenous peptides substantially enhance the ability of T cells to detect antigen, an effect measurable by up-regulation of activation or maturation markers and by increased effector function. This enhancement is most pronounced in thymocytes, moderate in naive T cells, and mild in effector T cells. The importance of endogenous peptides is inversely proportional to the agonist activity of the stimulatory peptide presented. Unlike for CD4+ T cells, the T cell receptor of CD8+ T cells does not distinguish between endogenous peptides for their ability to enhance antigen recognition.

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 Requirements for Peptide-induced T Cell Receptor Downregulation on Naive CD8+ T Cells

1997 ◽  
Vol 185 (4) ◽  
pp. 641-652 ◽  
Author(s):  
Zeling Cai ◽  
Hidehiro Kishimoto ◽  
Anders Brunmark ◽  
Michael R. Jackson ◽  
Per A. Peterson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Biological Significance ◽  
Cell Receptor ◽  
Metabolic Inhibitors ◽  
Histocompatibility Complex ◽  
Antigen Presenting

The requirements for inducing downregulation of α/β T cell receptor (TCR) molecules on naive major histocompatibility complex class I–restricted T cells was investigated with 2C TCR transgenic mice and defined peptides as antigen. Confirming previous results, activation of 2C T cells in response to specific peptides required CD8 expression on the responder cells and was heavily dependent upon costimulation provided by either B7-1 or ICAM-1 on antigen-presenting cells (APC). These stringent requirements did not apply to TCR downregulation. Thus, TCR downregulation seemed to depend solely on TCR/peptide/interaction and did not require either CD8 or B7-1 expression; ICAM-1 potentiated TCR downregulation, but only with limiting doses of peptides. TCR downregulation was most prominent with high affinity peptides and appeared to be neither obligatory nor sufficient for T cell activation. In marked contrast to T cell activation, TCR downregulation was resistant to various metabolic inhibitors. The biological significance of TCR downregulation is unclear, but could be a device for protecting T cells against excessive signaling.

Impact of myelin-specific antigen presenting B cells on T cell activation in multiple sclerosis

2008 ◽  
Vol 128 (3) ◽  
pp. 382-391 ◽  
Author(s):  
Christopher T. Harp ◽  
Amy E. Lovett-Racke ◽  
Michael K. Racke ◽  
Elliot M. Frohman ◽  
Nancy L. Monson
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Specific Antigen ◽  
Antigen Presenting

scholarly journals The B7-2 (B70) costimulatory molecule expressed by monocytes and activated B lymphocytes is the CD86 differentiation antigen

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1402-1407 ◽  
Author(s):  
P Engel ◽  
JG Gribben ◽  
GJ Freeman ◽  
LJ Zhou ◽  
Y Nozawa ◽  
...  
Keyword(s):  
T Cell ◽  
B Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Cell Receptor ◽  
Differentiation Antigen ◽  
Functional Assays ◽  
Antigen Presenting ◽  
Cluster Of Differentiation

Abstract T-cell activation is initiated after T-cell receptor binding to antigen, but also requires interactions between costimulatory molecules expressed on antigen-presenting cells. An important costimulatory molecule expressed by monocytes and activated B lymphocytes has been recently identified and termed B7–2 or B70. Independently, a new Cluster of Differentiation was defined in the Fifth International Leukocyte Differentiation Antigen Workshop as CD86, a molecule predominantly expressed by monocytes and activated B lymphocytes. In this study, the two monoclonal antibodies that defined CD86, FUN-1 and BU-63, were shown to bind to cDNA transfected cells expressing B7– 2/B70. The FUN-1 monoclonal antibody also completely blocked the costimulatory activity of B7–2/B70 in functional assays. Therefore, the serologically defined CD86 differentiation antigen is the B7–2/B70 molecule.

scholarly journals T cell activation requires force generation

2016 ◽  
Vol 213 (5) ◽  
pp. 535-542 ◽  
Author(s):  
Kenneth H. Hu ◽  
Manish J. Butte
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Calcium Flux ◽  
Force Microscopy ◽  
Atomic Force ◽  
Afm Cantilever ◽  
Antigen Presenting

Triggering of the T cell receptor (TCR) integrates both binding kinetics and mechanical forces. To understand the contribution of the T cell cytoskeleton to these forces, we triggered T cells using a novel application of atomic force microscopy (AFM). We presented antigenic stimulation using the AFM cantilever while simultaneously imaging with optical microscopy and measuring forces on the cantilever. T cells respond forcefully to antigen after calcium flux. All forces and calcium responses were abrogated upon treatment with an F-actin inhibitor. When we emulated the forces of the T cell using the AFM cantilever, even these actin-inhibited T cells became activated. Purely mechanical stimulation was not sufficient; the exogenous forces had to couple through the TCR. These studies suggest a mechanical–chemical feedback loop in which TCR-triggered T cells generate forceful contacts with antigen-presenting cells to improve access to antigen.

scholarly journals DNA-based nanoparticle tension sensors reveal that T-cell receptors transmit defined pN forces to their antigens for enhanced fidelity

2016 ◽  
Vol 113 (20) ◽  
pp. 5610-5615 ◽  
Author(s):  
Yang Liu ◽  
Lori Blanchfield ◽  
Victor Pui-Yan Ma ◽  
Rakieb Andargachew ◽  
Kornelia Galior ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Specific Response ◽  
Lymphocyte Function ◽  
Chemomechanical Coupling ◽  
Coreceptor Binding ◽  
Antigen Presenting

T cells are triggered when the T-cell receptor (TCR) encounters its antigenic ligand, the peptide-major histocompatibility complex (pMHC), on the surface of antigen presenting cells (APCs). Because T cells are highly migratory and antigen recognition occurs at an intermembrane junction where the T cell physically contacts the APC, there are long-standing questions of whether T cells transmit defined forces to their TCR complex and whether chemomechanical coupling influences immune function. Here we develop DNA-based gold nanoparticle tension sensors to provide, to our knowledge, the first pN tension maps of individual TCR-pMHC complexes during T-cell activation. We show that naïve T cells harness cytoskeletal coupling to transmit 12–19 pN of force to their TCRs within seconds of ligand binding and preceding initial calcium signaling. CD8 coreceptor binding and lymphocyte-specific kinase signaling are required for antigen-mediated cell spreading and force generation. Lymphocyte function-associated antigen 1 (LFA-1) mediated adhesion modulates TCR-pMHC tension by intensifying its magnitude to values >19 pN and spatially reorganizes the location of TCR forces to the kinapse, the zone located at the trailing edge of migrating T cells, thus demonstrating chemomechanical crosstalk between TCR and LFA-1 receptor signaling. Finally, T cells display a dampened and poorly specific response to antigen agonists when TCR forces are chemically abolished or physically “filtered” to a level below ∼12 pN using mechanically labile DNA tethers. Therefore, we conclude that T cells tune TCR mechanics with pN resolution to create a checkpoint of agonist quality necessary for specific immune response.

scholarly journals T-cell activation is modulated by the 3D mechanical microenvironment

2019 ◽  
Author(s):  
Fatemeh S. Majedi ◽  
Mohammad Mahdi Hasani-Sadrabadi ◽  
Timothy J. Thauland ◽  
Song Li ◽  
Louis-S. Bouchard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Mechanical Stiffness ◽  
Activation Markers ◽  
Cellular Pathways ◽  
And Migration ◽  
Antigen Presenting

AbstractT cells recognize mechanical forces through a variety of cellular pathways, including mechanical triggering of the T-cell receptor (TCR) and mechanical triggering of the integrin LFA-1. We show here that T cells can recognize forces arising from the rigidity of the microenvironment. We fabricated 3D hydrogels with mechanical stiffness tuned to 4 kPa and 40 kPa and specially engineered be microporous independent of stiffness. We cultured T cells and antigen presenting cells within the matrices and studied activation by flow cytometry and live imaging. We found there was an augmentation of T-cell activation in the context of mechanically stiffer 3D material as compared to the softer material. In contrast, proliferation, activation markers, and migration were all diminished in T cells cultured in the softer material. These results show that T cells can sense their mechanical environment and amplify responses in the context of mechanical stiffness.

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