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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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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. |
format | Online Article Text |
id | pubmed-4332248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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