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11 pages, 2322 KiB

Open AccessCommunication

Effect of Pharmacological Inhibition of the Catalytic Activity of Phosphatases of Regenerating Liver in Early T Cell Receptor Signaling Dynamics and IL-2 Production

by Oscar Aguilar-Sopeña, Sara Hernández-Pérez, Sergio Alegre-Gómez, Patricia Castro-Sánchez, Alba Iglesias-Ceacero, John S. Lazo and Pedro Roda-Navarro

Int. J. Mol. Sci. 2020, 21(7), 2530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072530 - 05 Apr 2020

Cited by 3 | Viewed by 2454

Abstract

We have previously shown the delivery of phosphatase of regenerating liver-1 (PRL-1) to the immunological synapse (IS) and proposed a regulatory role of the catalytic activity of PRLs (PRL-1, PRL-2 and PRL-3) in antigen-induced IL-2 production. Nonetheless, the expression in T cells and [...] Read more.

We have previously shown the delivery of phosphatase of regenerating liver-1 (PRL-1) to the immunological synapse (IS) and proposed a regulatory role of the catalytic activity of PRLs (PRL-1, PRL-2 and PRL-3) in antigen-induced IL-2 production. Nonetheless, the expression in T cells and delivery to the IS of the highly homologous PRL-3, as well as the role of the catalytic activity of PRLs in antigen-induced early signaling, has not been investigated. Here, the expression of PRL-3 protein was detected in primary CD4 T cells and in the CD4 T cell line Jurkat (JK), in which an overexpressed GFP-PRL-3 fluorescent fusion protein trafficked through the endosomal recycling compartment and co-localized with PLCγ1 signaling sites at the IS. Pharmacological inhibition was used to compare the role of the catalytic activity of PRLs in antigen-induced early signaling and late IL-2 production. Although the phosphatase activity of PRLs was not critical for early signaling triggered by antigen, it seemed to regulate signaling dynamics and was necessary for proper IL-2 production. We propose that enzymatic activity of PRLs has a higher significance for cytokine production than for early signaling at the IS. However, further research will be necessary to deeply understand the regulatory role of PRLs during lymphocyte activation and effector function. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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15 pages, 2262 KiB

Open AccessArticle

Various Stages of Immune Synapse Formation Are Differently Dependent on the Strength of the TCR Stimulus

by Michael Estl, Pascal Blatt, Xuemei Li, Ute Becherer, Hsin-Fang Chang, Jens Rettig and Varsha Pattu

Int. J. Mol. Sci. 2020, 21(7), 2475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072475 - 02 Apr 2020

Cited by 6 | Viewed by 2634

Abstract

Cytotoxic T lymphocytes (CTL) are key players of the adaptive immune system that target tumors and infected cells. A central step to that is the formation of a cell–cell contact zone between the CTL and its target called an immune synapse (IS). Here, [...] Read more.

Cytotoxic T lymphocytes (CTL) are key players of the adaptive immune system that target tumors and infected cells. A central step to that is the formation of a cell–cell contact zone between the CTL and its target called an immune synapse (IS). Here, we investigate the influence of the initial T cell receptor (TCR) trigger of a cytolytic IS on the distinct steps leading to cytotoxic granule (CG) exocytosis. We stimulated primary CTLs from mouse using lipid bilayers with varying anti-CD3 but constant ICAM concentrations. We fluorescently labeled molecular markers of distinct IS zones such as actin, CD3, granzyme B, and Synaptobrevin2 in CTLs and imaged cytolytic IS formation by total internal reflection fluorescence microscopy (TIRFM). We found that an intermediate anti-CD3 concentration of 10 µg/mL induces the fastest adhesion of CTLs to the bilayers and results in maximal CG fusion efficiency. The latency of actin ring formation, dwell time, and maximum surface area at the IS exhibit different dependencies on the stimulatory anti-CD3 concentrations. The number and surface area of CD3 clusters at the IS seem to show a different dependency to the TCR trigger when compared to their dwell time. Finally, the mode of full CG exocytosis appears to be independent of the TCR trigger. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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Review

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17 pages, 1760 KiB

Open AccessReview

Interplay Between SNX27 and DAG Metabolism in the Control of Trafficking and Signaling at the IS

by Natalia González-Mancha and Isabel Mérida

Int. J. Mol. Sci. 2020, 21(12), 4254; https://doi.org/10.3390/ijms21124254 - 15 Jun 2020

Cited by 5 | Viewed by 3703

Abstract

Recognition of antigens displayed on the surface of an antigen-presenting cell (APC) by T-cell receptors (TCR) of a T lymphocyte leads to the formation of a specialized contact between both cells named the immune synapse (IS). This highly organized structure ensures cell–cell communication [...] Read more.

Recognition of antigens displayed on the surface of an antigen-presenting cell (APC) by T-cell receptors (TCR) of a T lymphocyte leads to the formation of a specialized contact between both cells named the immune synapse (IS). This highly organized structure ensures cell–cell communication and sustained T-cell activation. An essential lipid regulating T-cell activation is diacylglycerol (DAG), which accumulates at the cell–cell interface and mediates recruitment and activation of proteins involved in signaling and polarization. Formation of the IS requires rearrangement of the cytoskeleton, translocation of the microtubule-organizing center (MTOC) and vesicular compartments, and reorganization of signaling and adhesion molecules within the cell–cell junction. Among the multiple players involved in this polarized intracellular trafficking, we find sorting nexin 27 (SNX27). This protein translocates to the T cell–APC interface upon TCR activation, and it is suggested to facilitate the transport of cargoes toward this structure. Furthermore, its interaction with diacylglycerol kinase ζ (DGKζ), a negative regulator of DAG, sustains the precise modulation of this lipid and, thus, facilitates IS organization and signaling. Here, we review the role of SNX27, DAG metabolism, and their interplay in the control of T-cell activation and establishment of the IS. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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16 pages, 2330 KiB

Open AccessReview

Connexin-Mediated Signaling at the Immunological Synapse

by Andrés Tittarelli, Mariela Navarrete, María Alejandra Gleisner, Peter Gebicke-Haerter and Flavio Salazar-Onfray

Int. J. Mol. Sci. 2020, 21(10), 3736; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103736 - 25 May 2020

Cited by 17 | Viewed by 4846

Abstract

The immunological synapse (IS) is an intercellular communication platform, organized at the contact site of two adjacent cells, where at least one is an immune cell. Functional IS formation is fundamental for the modulation of the most relevant immune system activities, such as [...] Read more.

The immunological synapse (IS) is an intercellular communication platform, organized at the contact site of two adjacent cells, where at least one is an immune cell. Functional IS formation is fundamental for the modulation of the most relevant immune system activities, such as T cell activation by antigen presenting cells and T cell/natural killer (NK) cell-mediated target cell (infected or cancer) killing. Extensive evidence suggests that connexins, in particular connexin-43 (Cx43) hemichannels and/or gap junctions, regulate signaling events in different types of IS. Although the underlying mechanisms are not fully understood, the current evidence suggests that Cx43 channels could act as facilitators for calcium ions, cyclic adenosine monophosphate, and/or adenosine triphosphate uptake and/or release at the interface of interacting cells. These second messengers have relevant roles in the IS signaling during dendritic cell-mediated T and NK cell activation, regulatory T cell-mediated immune suppression, and cytotoxic T lymphocyte or NK cell-mediated target tumor cell killing. Additionally, as the cytoplasmic C-terminus domain of Cx43 interacts with a plethora of proteins, Cx43 may act as scaffolds for integration of various regulatory proteins at the IS, as suggested by the high number of Cx43-interacting proteins that translocate at these cell-cell interface domains. In this review, we provide an updated overview and analysis on the role and possible underlying mechanisms of Cx43 in IS signaling. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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17 pages, 1240 KiB

Open AccessReview

Spatiotemporal Regulation of Signaling: Focus on T Cell Activation and the Immunological Synapse

by Esther Garcia and Shehab Ismail

Int. J. Mol. Sci. 2020, 21(9), 3283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093283 - 06 May 2020

Cited by 21 | Viewed by 5615

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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14 pages, 929 KiB

Open AccessReview

The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation

by Sara G. Dosil, Amelia Rojas-Gomez, Francisco Sánchez-Madrid and Noa B. Martín-Cófreces

Int. J. Mol. Sci. 2020, 21(8), 2859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082859 - 19 Apr 2020

Cited by 1 | Viewed by 6760

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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17 pages, 980 KiB

Open AccessReview

Modes of Communication between T Cells and Relevance for Immune Responses

by Lion F. K. Uhl and Audrey Gérard

Int. J. Mol. Sci. 2020, 21(8), 2674; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082674 - 11 Apr 2020

Cited by 8 | Viewed by 4618

Abstract

T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they [...] Read more.

T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response—stochastic on the individual cell level, robust on the global level—necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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21 pages, 1207 KiB

Open AccessReview

Inducible Polarized Secretion of Exosomes in T and B Lymphocytes

by Victor Calvo and Manuel Izquierdo

Int. J. Mol. Sci. 2020, 21(7), 2631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072631 - 10 Apr 2020

Cited by 34 | Viewed by 5505

Abstract

Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and [...] Read more.

Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and a limited number of cell surface receptors. Among these, exosome secretion is induced in T lymphocytes and B lymphocytes when stimulated at the immune synapse (IS) via T-cell receptors (TCR) and B-cell receptors (BCR), respectively. IS formation by T and B lymphocytes constitutes a crucial event involved in antigen-specific, cellular, and humoral immune responses. Upon IS formation by T and B lymphocytes with antigen-presenting cells (APC), the convergence of MVB towards the microtubule organization center (MTOC), and MTOC polarization to the IS, are involved in polarized exosome secretion at the synaptic cleft. This specialized mechanism provides the immune system with a finely-tuned strategy to increase the specificity and efficiency of crucial secretory effector functions of B and T lymphocytes. As inducible exosome secretion by antigen-receptors is a critical and unique feature of the immune system this review considers the study of the traffic events leading to polarized exosome secretion at the IS and some of their biological consequences. Full article

(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)

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