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Researchers map the intracellular wiring of the immune system for the first time

Written by Miyako Rogers, Science Writer

In a new study published in Nature, researchers have developed a first-of-its-kind map detailing the network of connections that make up our immune system. A new invaluable resource, this map could help develop therapeutic treatments such as immunotherapy and shed light on basic discovery science, such as analysing how immune cell networks are altered in specific diseases.

Immune cells are constantly travelling around the human body, forming connections and communicating with each other in a complex and dynamic network. This constant communication is vital for maintaining our immune system, is essential in fighting off disease and is implicated in the development of auto-immune diseases, such as multiple sclerosis. By systematically mapping these connections, researchers can now gain an unprecedented level of information and understanding about different biological processes and diseases.

Building the map

To build the map, researchers first tested protein-protein interactions using a SAVEXIS (scalable arrayed multi-valent extracellular interaction screen), a type of high-throughput screening they developed for this purpose. They then independently checked each newly discovered protein-protein interaction to provide information about the biophysical characteristics of each connection. This protein interactome was then integrated with single-cell genomic datasets of different human tissues, creating a multi-organ map of interactions.

Figure 1 ¦ Schematic summarising immune receptor interactions

Finally, the researchers assigned functions to different connections by targeted stimulation of specific proteins in human immune cells and then analysed the proteins with multiplex high-content microscopy. In this way, the researchers created a comprehensive map of connections in the immune system. The scale in creating a map of this size and detail should not be understated; there are hundreds of distinct surface proteins on each immune cell and protein-protein interactions are often transient, hence the need to develop SAVEXIS.

Implications for the future

This map systematically documents and describes the intracellular wiring of the immune system, from cell-cell connections down to the biophysical properties of surface proteins. In this study alone, researchers identified several potential therapeutic targets. For example, they identified major histocompatibility complexes HLA-E and HLA-F as ligands for immune checkpoint receptor VISTA (V-domain immunoglobulin suppressor of T cell activation). They also highlighted the SLITRK4 pathway in lymphocyte responses as a pathway that should require further investigation.

However, this map has future applications beyond the scope of this study. The methods and strategies used to develop this map, such as SAVEXIS, could be used in future research to map other cellular networks in the human body. Furthermore, by disentangling the intracellular wiring of the immune system, this resource could prove invaluable for future research and the development of immunotherapies.

More on these topics

Immune System / Multi-omics / Proteomics