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Retrograde and Anterograde Transport of Lat-Vesicles during the Immunological Synapse Formation: Defining the Finely-Tuned Mechanism
 
 
Article

A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability

1
School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK
2
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3
Immunology Therapeutic Area, UCB, Slough, SL1 3WE, UK
4
R&D Oncology, AstraZeneca, Granta Park, Cambridge, CB21 6GH, UK
5
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, UK
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Gerhard J. Schütz and Johannes Huppa
Cells 2021, 10(2), 418; https://doi.org/10.3390/cells10020418
Received: 2 December 2020 / Revised: 12 February 2021 / Accepted: 12 February 2021 / Published: 17 February 2021
(This article belongs to the Special Issue Molecular Mechanisms of Early T Cell Signaling)
Peripheral immune regulation is critical for the maintenance of self-tolerance. Here we have investigated signaling processes that distinguish T cells with regulatory capability from effector T cells. The murine Tg4 T cell receptor recognizes a peptide derived from the self-antigen myelin basic protein. T cells from Tg4 T cell receptor transgenic mice can be used to generate effector T cells and three types of T cells with regulatory capability, inducible regulatory T cells, T cells tolerized by repeated in vivo antigenic peptide exposure or T cells treated with the tolerogenic drug UCB9608 (a phosphatidylinositol 4 kinase IIIβ inhibitor). We comparatively studied signaling in all of these T cells by activating them with the same antigen presenting cells presenting the same myelin basic protein peptide. Supramolecular signaling structures, as efficiently detected by large-scale live cell imaging, are critical mediators of T cell activation. The formation of a supramolecular signaling complex anchored by the adaptor protein linker for activation of T cells (LAT) was consistently terminated more rapidly in Tg4 T cells with regulatory capability. Such termination could be partially reversed by blocking the inhibitory receptors CTLA-4 and PD-1. Our work suggests that attenuation of proximal signaling may favor regulatory over effector function in T cells. View Full-Text
Keywords: regulatory T cell; tolerance; immunological synapse; central supramolecular activation cluster (cSMAC); supramolecular signaling complex; linker for activation of T cells (LAT); inhibitory receptors; CTLA-4; PD-1 regulatory T cell; tolerance; immunological synapse; central supramolecular activation cluster (cSMAC); supramolecular signaling complex; linker for activation of T cells (LAT); inhibitory receptors; CTLA-4; PD-1
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MDPI and ACS Style

Li, Y.; Tunbridge, H.M.; Britton, G.J.; Hill, E.V.; Sinai, P.; Cirillo, S.; Thompson, C.; Fallah-Arani, F.; Dovedi, S.J.; Wraith, D.C.; Wülfing, C. A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability. Cells 2021, 10, 418. https://doi.org/10.3390/cells10020418

AMA Style

Li Y, Tunbridge HM, Britton GJ, Hill EV, Sinai P, Cirillo S, Thompson C, Fallah-Arani F, Dovedi SJ, Wraith DC, Wülfing C. A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability. Cells. 2021; 10(2):418. https://doi.org/10.3390/cells10020418

Chicago/Turabian Style

Li, Yikui, Helen M. Tunbridge, Graham J. Britton, Elaine V. Hill, Parisa Sinai, Silvia Cirillo, Clare Thompson, Farnaz Fallah-Arani, Simon J. Dovedi, David C. Wraith, and Christoph Wülfing. 2021. "A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability" Cells 10, no. 2: 418. https://doi.org/10.3390/cells10020418

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