scholarly journals T-Cell Receptor Microclusters Critical for T-Cell Activation Are Formed Independently of Lipid Raft Clustering

2010 ◽  
Vol 30 (14) ◽  
pp. 3421-3429 ◽  
Author(s):  
Akiko Hashimoto-Tane ◽  
Tadashi Yokosuka ◽  
Chitose Ishihara ◽  
Machie Sakuma ◽  
Wakana Kobayashi ◽  
...  
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Lipid Raft ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Resonance Energy ◽  
Careful Analysis ◽  
Cell Receptor

ABSTRACT We studied the function of lipid rafts in generation and signaling of T-cell receptor microclusters (TCR-MCs) and central supramolecular activation clusters (cSMACs) at immunological synapse (IS). It has been suggested that lipid raft accumulation creates a platform for recruitment of signaling molecules upon T-cell activation. However, several lipid raft probes did not accumulate at TCR-MCs or cSMACs even with costimulation and the fluorescence resonance energy transfer (FRET) between TCR or LAT and lipid raft probes was not induced at TCR-MCs under the condition of positive induction of FRET between CD3ζ and ZAP-70. The analysis of LAT mutants revealed that raft association is essential for the membrane localization but dispensable for TCR-MC formation. Careful analysis of the accumulation of raft probes in the cell interface revealed that their accumulation occurred after cSMAC formation, probably due to membrane ruffling and/or endocytosis. These results suggest that lipid rafts control protein translocation to the membrane but are not involved in the clustering of raft-associated molecules and therefore that the lipid rafts do not serve as a platform for T-cell activation.

scholarly journals Surface Cytotoxic T Lymphocyte–associated Antigen 4 Partitions Within Lipid Rafts and Relocates to the Immunological Synapse under Conditions of Inhibition of T Cell Activation

2002 ◽  
Vol 195 (10) ◽  
pp. 1337-1347 ◽  
Author(s):  
Peter J. Darlington ◽  
Miren L. Baroja ◽  
Thu A. Chau ◽  
Eric Siu ◽  
Vincent Ling ◽  
...  
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Lipid Raft ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Subcellular Fractionation

T cell activation through the T cell receptor (TCR) involves partitioning of receptors into discrete membrane compartments known as lipid rafts, and the formation of an immunological synapse (IS) between the T cell and antigen-presenting cell (APC). Compartmentalization of negative regulators of T cell activation such as cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) is unknown. Recent crystal structures of B7-ligated CTLA-4 suggest that it may form lattices within the IS which could explain the mechanism of action of this molecule. Here, we show that after T cell stimulation, CTLA-4 coclusters with the TCR and the lipid raft ganglioside GM1 within the IS. Using subcellular fractionation, we show that most lipid raft-associated CTLA-4 is on the T cell surface. Such compartmentalization is dependent on the cytoplasmic tail of CTLA-4 and can be forced with a glycosylphosphatidylinositol-anchor in CTLA-4. The level of CTLA-4 within lipid rafts increases under conditions of APC-dependent TCR–CTLA-4 coligation and T cell inactivation. However, raft localization, although necessary for inhibition of T cell activation, is not sufficient for CTLA-4–mediated negative signaling. These data demonstrate that CTLA-4 within lipid rafts migrates to the IS where it can potentially form lattice structures and inhibit T cell activation.

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.

Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation

2015 ◽  
Vol 396 (6-7) ◽  
pp. 749-758 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Nora Müller
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Activity ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Functional Responses

Abstract Host T cell activation, a key step in obtaining adaptive immunity against pathogens, is initiated by the binding of the T cell receptor to a foreign antigenic peptide presented by the major histocompatibility complex on the surface of an antigen-presenting cell and, consequently, formation of an immunological synapse. Within the immunological synapse, the engagement of the T cell receptor in cooperation with simultaneous ligation of co-stimulatory molecules induces a precisely organized cascade of signaling events and pathways that regulate clonal expansion and differentiation of naïve T cells into effector T cells contributing to pathogen clearance. The biochemical changes that underlie T cell activation and differentiation, however, not only involve proteins but also lipids. In particular, catabolic cleavage of sphingomyelin generating ceramide can substantially influence functional responses in cells of the immune system. Changes in sphingomyelin and ceramide content have been reported to directly impact on membrane physiology, thus modifying signal transmission and interfering with diverse aspects of T cell activity. In this review we will focus on sphingomyelin breakdown/ceramide generation in T cells with regard to their function and development of T cell-mediated immunity.

scholarly journals Negative Regulation of T Cell Receptor–Lipid Raft Interaction by Cytotoxic T Lymphocyte–associated Antigen 4

2003 ◽  
Vol 197 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Shunsuke Chikuma ◽  
John B. Imboden ◽  
Jeffrey A. Bluestone
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Signaling Complex

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is an essential negative regulator of T cell activation. Recent evidence suggests that CTLA-4 association with the immunological synapse during contact with antigen-presenting cells is important for its inhibitory function. In the present study, we observed a direct interaction of CTLA-4 with the phosphorylated form of T cell receptor (TCR)ζ within the glycolipid-enriched microdomains associated with the T cell signaling complex. In this setting, CTLA-4 regulated the accumulation/retention of TCRζ in the signaling complex, as the lipid raft fractions from CTLA-4KO T cells contained significantly higher amounts of the TCR components when compared with wild-type littermates. In contrast, coligation of CTLA-4 with the TCR during T cell activation selectively decreased the amount of TCRζ that accumulated in the rafts. These results suggest that CTLA-4 functions to regulate T cell signaling by controlling TCR accumulation and/or retention within this a critical component of the immunological synapse.

scholarly journals HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

2016 ◽  
Vol 90 (23) ◽  
pp. 10513-10526 ◽  
Author(s):  
Jing Deng ◽  
Yu-ya Mitsuki ◽  
Guomiao Shen ◽  
Jocelyn C. Ray ◽  
Claudia Cicala ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Activation Process ◽  
Hiv Envelope

ABSTRACTHIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.IMPORTANCEThere are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.

scholarly journals Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

2008 ◽  
Vol 19 (7) ◽  
pp. 2802-2817 ◽  
Author(s):  
Valarie A. Barr ◽  
Kelsie M. Bernot ◽  
Sonal Srikanth ◽  
Yousang Gwack ◽  
Lakshmi Balagopalan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Dynamic Movement ◽  
Immunological Synapses

The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca2+ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca2+ channel components to existing and newly forming immunological synapses.

scholarly journals Phosphoinositide 3–kinase γ participates in T cell receptor–induced T cell activation

2007 ◽  
Vol 204 (12) ◽  
pp. 2977-2987 ◽  
Author(s):  
Isabela Alcázar ◽  
Miriam Marqués ◽  
Amit Kumar ◽  
Emilio Hirsch ◽  
Matthias Wymann ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Class I ◽  
T Cell Stimulation ◽  
Phosphoinositide 3 Kinase ◽  
Antigen Presenting

Class I phosphoinositide 3–kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase–associated receptors or G protein–coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class IA p85/p110 heterodimers, which are activated by Tyr kinases, and the class IB p110γ isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110γ deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110γ, as well as the consequences of interfering with p110γ expression or function for T cell activation. We found that after TCR ligation, p110γ interacts with Gαq/11, lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation.

scholarly journals Flotillins promote T cell receptor sorting through a fast Rab5–Rab11 endocytic recycling axis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Gregory M. I. Redpath ◽  
Manuela Ecker ◽  
Natasha Kapoor-Kaushik ◽  
Haig Vartoukian ◽  
Michael Carnell ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Fluorescent Proteins ◽  
Cell Receptor ◽  
Endocytic Recycling ◽  
Recycling Endosomes ◽  
Comprehensive Picture

Abstract The targeted endocytic recycling of the T cell receptor (TCR) to the immunological synapse is essential for T cell activation. Despite this, the mechanisms that underlie the sorting of internalised receptors into recycling endosomes remain poorly understood. To build a comprehensive picture of TCR recycling during T cell activation, we developed a suite of new imaging and quantification tools centred on photoactivation of fluorescent proteins. We show that the membrane-organising proteins, flotillin-1 and -2, are required for TCR to reach Rab5-positive endosomes immediately after endocytosis and for transfer from Rab5- to Rab11a-positive compartments. We further observe that after sorting into in Rab11a-positive vesicles, TCR recycles to the plasma membrane independent of flotillin expression. Our data suggest a mechanism whereby flotillins delineate a fast Rab5-Rab11a endocytic recycling axis and functionally contribute to regulate the spatial organisation of these endosomes.

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