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F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse

Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Her...

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Detalles Bibliográficos
Autores principales: Comrie, William A., Babich, Alexander, Burkhardt, Janis K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332248/
https://www.ncbi.nlm.nih.gov/pubmed/25666810
http://dx.doi.org/10.1083/jcb.201406121
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author Comrie, William A.
Babich, Alexander
Burkhardt, Janis K.
author_facet Comrie, William A.
Babich, Alexander
Burkhardt, Janis K.
author_sort Comrie, William A.
collection PubMed
description Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse.
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spelling pubmed-43322482015-08-16 F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse Comrie, William A. Babich, Alexander Burkhardt, Janis K. J Cell Biol Research Articles Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse. The Rockefeller University Press 2015-02-16 /pmc/articles/PMC4332248/ /pubmed/25666810 http://dx.doi.org/10.1083/jcb.201406121 Text en © 2015 Comrie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Comrie, William A.
Babich, Alexander
Burkhardt, Janis K.
F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title_full F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title_fullStr F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title_full_unstemmed F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title_short F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
title_sort f-actin flow drives affinity maturation and spatial organization of lfa-1 at the immunological synapse
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332248/
https://www.ncbi.nlm.nih.gov/pubmed/25666810
http://dx.doi.org/10.1083/jcb.201406121
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