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 Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+Regulatory T Cells

2012 ◽  
Vol 287 (14) ◽  
pp. 11098-11107 ◽  
Author(s):  
Jozsef Karman ◽  
Ji-Lei Jiang ◽  
Nathan Gumlaw ◽  
Hongmei Zhao ◽  
Juanita Campos-Rivera ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocyte Antigen

scholarly journals Disc Large Homolog 1 Is Critical for Early T Cell Receptor Micro Cluster Formation and Activation in Human T Cells

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1446
Author(s):  
June Guha ◽  
Raj Chari
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
T Cell Signaling

T cell activation by antigen involves multiple sequential steps, including T cell receptor-microcluster TCR-(MC) formation, immunological synapse formation, and phosphorylation of mediators downstream of the TCR. The adaptor protein, Disc Large Homolog 1 (DLG1), is known to regulate proximal TCR signaling and, in turn, T cell activation, acting as a molecular chaperone that organizes specific kinases downstream of antigen recognition. In this study, we used knockdown and knockout technologies in human primary T cells and a human T cell line to demonstrate the role of DLG1 in proximal T cell signaling. High-end confocal microscopy was used for pictorial representation of T cell micro-clusters and colocalization studies. From all these studies, we could demonstrate that DLG1 functions even earlier than immunological synapse formation, to regulate T cell activation by promoting TCR-MC formation. Moreover, we found that DLG1 can act as a bridge between the TCR-ζ chain and ZAP70 while inhibiting binding of the phosphatase SHP1 to TCR-ζ. Together, these effects drive dysregulation of T cell activation in DLG1-deficient T cells. Overall, the activation and survival status of T cell is a critical determinant of effective vaccine response, and DLG1-mediated T cell signaling events can be a driving factor for improving vaccine-designing strategies.

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.

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Science ◽  
2021 ◽  
Vol 372 (6546) ◽  
pp. eabe9124
Author(s):  
Pirooz Zareie ◽  
Christopher Szeto ◽  
Carine Farenc ◽  
Sachith D. Gunasinghe ◽  
Elizabeth M. Kolawole ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Signaling ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Direct Consequence ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Cell Repertoire

T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRβ-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

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 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.

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 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 B7-1 Engagement of Cytotoxic T Lymphocyte Antigen 4 Inhibits T Cell Activation in the Absence of CD28

1998 ◽  
Vol 188 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Francesca Fallarino ◽  
Patrick E. Fields ◽  
Thomas F. Gajewski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
Lymphocyte Antigen

Ligation of cytotoxic T lymphocyte antigen 4 (CTLA4) appears to inhibit T cell responses. Four mechanisms have been proposed to explain the inhibitory activity of CTLA4: competition for B7-1 and B7-2 binding by CD28; sequestration of signaling molecules away from CD28 via endocytosis; delivery of a signal that antagonizes a CD28 signal; and delivery of a signal that antagonizes a T cell receptor (TCR) signal. As three of these potential mechanisms involve functional antagonism of CD28, an experimental model was designed to determine whether CTLA4 could inhibit T cell function in the absence of CD28. TCR transgenic/recombinase activating gene 2–deficient/CD28–wild-type or CD28-deficient mice were generated and immunized with an antigen-expressing tumor. Primed T cells from both types of mice produced cytokines and proliferated in response to stimulator cells lacking B7 expression. However, whereas the response of CD28+/+ T cells was augmented by costimulation with B7-1, the response of the CD28−/− T cells was strongly inhibited. This inhibition was reversed by monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.

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