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A physical wiring diagram for the human immune system.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Galaway, Francis 
Müller-Sienerth, Nicole  ORCID logo  https://orcid.org/0000-0002-7527-5127
Chong, Zheng-Shan 

Abstract

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 proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. 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.

Description

Keywords

Cell Communication, Humans, Immune System, Leukocytes, Protein Binding, Protein Interaction Maps, Proteome, Receptors, Cell Surface

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

608

Publisher

Springer Science and Business Media LLC