scholarly journals The Novel PKCθfrom Benchtop to Clinic

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Rouba Hage-Sleiman ◽  
Asmaa B. Hamze ◽  
Lina Reslan ◽  
Hadile Kobeissy ◽  
Ghassan Dbaibo
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Catalytic Domain ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
The Novel ◽  
Cellular Processes ◽  
Downstream Effectors ◽  
Preclinical And Clinical Studies

The protein kinases C (PKCs) are a family of serine/threonine kinases involved in regulating multiple essential cellular processes such as survival, proliferation, and differentiation. Of particular interest is the novel, calcium-independent PKCθwhich plays a central role in immune responses. PKCθshares structural similarities with other PKC family members, mainly consisting of an N-terminal regulatory domain and a C-terminal catalytic domain tethered by a hinge region. This isozyme, however, is unique in that it translocates to the immunological synapse between a T cell and an antigen-presenting cell (APC) upon T cell receptor-peptide MHC recognition. Thereafter, PKCθinteracts physically and functionally with downstream effectors to mediate T cell activation and differentiation, subsequently leading to inflammation. PKCθ-specific perturbations have been identified in several diseases, most notably autoimmune disorders, and hence the modulation of its activity presents an attractive therapeutic intervention. To that end, many inhibitors of PKCs and PKCθhave been developed and tested in preclinical and clinical studies. And although selectivity remains a challenge, results are promising for the future development of effective PKCθinhibitors that would greatly advance the treatment of several T-cell mediated diseases.

scholarly journals Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse

2013 ◽  
Vol 210 (11) ◽  
pp. 2415-2433 ◽  
Author(s):  
Helena Soares ◽  
Ricardo Henriques ◽  
Martin Sachse ◽  
Leandro Ventimiglia ◽  
Miguel A. Alonso ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Fine Tuning ◽  
Synaptic Membrane ◽  
Vesicular Traffic ◽  
Tcr Signal Transduction

How the vesicular traffic of signaling molecules contributes to T cell receptor (TCR) signal transduction at the immunological synapse remains poorly understood. In this study, we show that the protein tyrosine kinase Lck, the TCRζ subunit, and the adapter LAT traffic through distinct exocytic compartments, which are released at the immunological synapse in a differentially regulated manner. Lck vesicular release depends on MAL protein. Synaptic Lck, in turn, conditions the calcium- and synaptotagmin-7–dependent fusion of LAT and TCRζ containing vesicles. Fusion of vesicles containing TCRζ and LAT at the synaptic membrane determines not only the nanoscale organization of phosphorylated TCRζ, ZAP70, LAT, and SLP76 clusters but also the presence of phosphorylated LAT and SLP76 in interacting signaling nanoterritories. This mechanism is required for priming IL-2 and IFN-γ production and may contribute to fine-tuning T cell activation breadth in response to different stimulatory conditions.

scholarly journals Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation

2004 ◽  
Vol 199 (3) ◽  
pp. 369-379 ◽  
Author(s):  
Magdalena M. Gorska ◽  
Susan J. Stafford ◽  
Osman Cen ◽  
Sanjiv Sur ◽  
Rafeul Alam
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
The Novel ◽  
Tcr Signaling ◽  
Src Homology

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex.

scholarly journals Micro–adhesion rings surrounding TCR microclusters are essential for T cell activation

2016 ◽  
Vol 213 (8) ◽  
pp. 1609-1625 ◽  
Author(s):  
Akiko Hashimoto-Tane ◽  
Machie Sakuma ◽  
Hiroshi Ike ◽  
Tadashi Yokosuka ◽  
Yayoi Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adhesion Molecules ◽  
Focal Adhesion ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Ring Structure ◽  
Cell Functions

The immunological synapse (IS) formed at the interface between T cells and antigen-presenting cells represents a hallmark of initiation of acquired immunity. T cell activation is initiated at T cell receptor (TCR) microclusters (MCs), in which TCRs and signaling molecules assemble at the interface before IS formation. We found that each TCR-MC was transiently bordered by a ring structure made of integrin and focal adhesion molecules in the early phase of activation, which is similar in structure to the IS in microscale. The micro–adhesion ring is composed of LFA-1, focal adhesion molecules paxillin and Pyk2, and myosin II (MyoII) and is supported by F-actin core and MyoII activity through LFA-1 outside-in signals. The formation of the micro–adhesion ring was transient but especially sustained upon weak TCR stimulation to recruit linker for activation of T cells (LAT) and SLP76. Perturbation of the micro–adhesion ring induced impairment of TCR-MC development and resulted in impaired cellular signaling and cell functions. Thus, the synapse-like structure composed of the core TCR-MC and surrounding micro–adhesion ring is a critical structure for initial T cell activation through integrin outside-in signals.

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.

The actin cloud induced by LFA-1–mediated outside-in signals lowers the threshold for T-cell activation

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 168-175 ◽  
Author(s):  
Jun-ichiro Suzuki ◽  
Sho Yamasaki ◽  
Jennifer Wu ◽  
Gary A. Koretzky ◽  
Takashi Saito
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Cloud Formation ◽  
Lymphocyte Function ◽  
Tcr Signaling

Abstract The dynamic rearrangement of the actin cytoskeleton plays critical roles in T-cell receptor (TCR) signaling and immunological synapse (IS) formation in T cells. Following actin rearrangement in T cells upon TCR stimulation, we found a unique ring-shaped reorganization of actin called the “actin cloud,” which was specifically induced by outside-in signals through lymphocyte function–associated antigen-1 (LFA-1) engagement. In T-cell–antigen-presenting cell (APC) interactions, the actin cloud is generated in the absence of antigen and localized at the center of the T-cell–APC interface, where it accumulates LFA-1 and tyrosine-phosphorylated proteins. The LFA-1–induced actin cloud formation involves ADAP (adhesion- and degranulation-promoting adaptor protein) phosphorylation, LFA-1/ADAP assembly, and c-Jun N-terminal kinase (JNK) activation, and occurs independent of TCR and its proximal signaling. The formation of the actin cloud lowers the threshold for subsequent T-cell activation. Thus, the actin cloud induced by LFA-1 engagement may serve as a possible platform for LFA-1–mediated costimulatory function for T-cell activation.

scholarly journals The Ca2+-activated K+ channel KCa3.1 compartmentalizes in the immunological synapse of human T lymphocytes

2007 ◽  
Vol 292 (4) ◽  
pp. C1431-C1439 ◽  
Author(s):  
Stella A. Nicolaou ◽  
Lisa Neumeier ◽  
YouQing Peng ◽  
Daniel C. Devor ◽  
Laura Conforti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
K Channel ◽  
Activated T Cells ◽  
Barr Virus

T cell receptor engagement results in the reorganization of intracellular and membrane proteins at the T cell-antigen presenting cell interface forming the immunological synapse (IS), an event required for Ca2+ influx. KCa3.1 channels modulate Ca2+ signaling in activated T cells by regulating the membrane potential. Nothing is known regarding KCa3.1 membrane distribution during T cell activation. Herein, we determined whether KCa3.1 translocates to the IS in human T cells using YFP-tagged KCa3.1 channels. These channels showed electrophysiological and pharmacological properties identical to wild-type channels. IS formation was induced by either anti-CD3/CD28 antibody-coated beads for fixed microscopy experiments or Epstein-Barr virus-infected B cells for fixed and live cell microscopy. In fixed microscopy experiments, T cells were also immunolabeled for F-actin or CD3ε, which served as IS formation markers. The distribution of KCa3.1 was determined with confocal and fluorescence microscopy. We found that, upon T cell activation, KCa3.1 channels localize with F-actin and CD3ε to the IS but remain evenly distributed on the cell membrane when no stimulus is provided. Detailed imaging experiments indicated that KCa3.1 channels are recruited in the IS shortly after antigen presentation and are maintained there for at least 15–30 min. Interestingly, pretreatment of activated T cells with the specific KCa3.1 blocker TRAM-34 blocked Ca2+ influx, but channel redistribution to the IS was not prevented. These results indicate that KCa3.1 channels are a part of the signaling complex that forms at the IS upon antigen presentation.

scholarly journals Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiyuan Gao ◽  
Yuedi Wang ◽  
Feifei Luo ◽  
Yiwei Chu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcomes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
T Cell Response ◽  
Antigen Receptors ◽  
Cell Therapies

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.

scholarly journals IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

2011 ◽  
Vol 208 (12) ◽  
pp. 2545-2560 ◽  
Author(s):  
Hye-Ran Kim ◽  
Byeong-Hun Jeon ◽  
Hyun-Su Lee ◽  
Sin-Hyeog Im ◽  
Masatake Araki ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Transmembrane Domain ◽  
Cell Receptor ◽  
Immunoglobulin Superfamily ◽  
Tcr Signaling ◽  
Cell Functions ◽  
Cell Immunity

Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8+ T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell–APC interaction.

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.

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