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A physical wiring diagram for the human immune system

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes(1). Despite their therapeutic potential(2), our map of these surface intera...

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Autores principales: Shilts, Jarrod, Severin, Yannik, Galaway, Francis, Müller-Sienerth, Nicole, Chong, Zheng-Shan, Pritchard, Sophie, Teichmann, Sarah, Vento-Tormo, Roser, Snijder, Berend, Wright, Gavin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365698/
https://www.ncbi.nlm.nih.gov/pubmed/35922511
http://dx.doi.org/10.1038/s41586-022-05028-x
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author Shilts, Jarrod
Severin, Yannik
Galaway, Francis
Müller-Sienerth, Nicole
Chong, Zheng-Shan
Pritchard, Sophie
Teichmann, Sarah
Vento-Tormo, Roser
Snijder, Berend
Wright, Gavin J.
author_facet Shilts, Jarrod
Severin, Yannik
Galaway, Francis
Müller-Sienerth, Nicole
Chong, Zheng-Shan
Pritchard, Sophie
Teichmann, Sarah
Vento-Tormo, Roser
Snijder, Berend
Wright, Gavin J.
author_sort Shilts, Jarrod
collection PubMed
description The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes(1). Despite their therapeutic potential(2), our map of these surface interactions remains incomplete(3,4). Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.
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spelling pubmed-93656982022-08-12 A physical wiring diagram for the human immune system Shilts, Jarrod Severin, Yannik Galaway, Francis Müller-Sienerth, Nicole Chong, Zheng-Shan Pritchard, Sophie Teichmann, Sarah Vento-Tormo, Roser Snijder, Berend Wright, Gavin J. Nature Article The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes(1). Despite their therapeutic potential(2), our map of these surface interactions remains incomplete(3,4). Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention. Nature Publishing Group UK 2022-08-03 2022 /pmc/articles/PMC9365698/ /pubmed/35922511 http://dx.doi.org/10.1038/s41586-022-05028-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shilts, Jarrod
Severin, Yannik
Galaway, Francis
Müller-Sienerth, Nicole
Chong, Zheng-Shan
Pritchard, Sophie
Teichmann, Sarah
Vento-Tormo, Roser
Snijder, Berend
Wright, Gavin J.
A physical wiring diagram for the human immune system
title A physical wiring diagram for the human immune system
title_full A physical wiring diagram for the human immune system
title_fullStr A physical wiring diagram for the human immune system
title_full_unstemmed A physical wiring diagram for the human immune system
title_short A physical wiring diagram for the human immune system
title_sort physical wiring diagram for the human immune system
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365698/
https://www.ncbi.nlm.nih.gov/pubmed/35922511
http://dx.doi.org/10.1038/s41586-022-05028-x
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