The number of proteins from each class is noted above, and the recombinant expression strategy is illustrated below. b, Schematic showing the diverse structural architectures of leukocyte surface proteins within the pan-leukocyte library of 630 proteins. Without a systematic picture of the physical interactions that link immune cells, any efforts at present to generate truly systems-level views of immune function will remain patchwork at best.Ī, SAVEXIS enables efficient and high-throughput screening for protein binding interactions between recombinant extracellular domains. Moreover, many immune receptors of clinical importance have been left as ‘orphans’, with their physiological ligands undiscovered despite in some cases decades of study 19, 20, 21, 22. Thus, how complete our understanding is of extracellular immune receptor interactions has remained unknown. These methods, however, generally lack the throughput to systematically characterize whole cell-surface proteomes, or have only had success for specific protein families rather than the full diverse spectrum of surface protein topologies and complexes 17, 18. Specialized methods have been developed that tackle individual challenges stemming from membrane-embedded surface proteins, such as their typically weak binding affinities 13, 14 and the low tractability of these proteins for many classic biochemical approaches 15, 16. For these reasons, along with their accessibility to systemically administered medicines, immune surface proteins and their interactions are particularly attractive therapeutic targets 2, 8.Īlthough the interaction networks that involve secreted proteins have already been systematically catalogued 9, 10, in the immune system and more generally across existing protein interaction databases, there remains a substantial under-representation of the interactions between cell-surface proteins 11, 12. Consequently, immune receptors regulate virtually all stages of cellular activation and are appreciated as critical mediators of a variety of homeostatic and pathological processes, which range from tumour surveillance, to autoimmunity, to infection control. The immune system has been described from one perspective as carefully coordinated networks of cell types 6, 7, where by extension it is these physical linkages that hold the network together 3. Diverse arrays of cell-surface proteins organize immune cells into interconnected cellular communities, linking cells through physical interactions that act both for signalling communication and for structural adhesion 5. The human immune system must maintain the same coordination and cohesion as the body’s other homeostatic organ systems despite being composed of highly migratory and circulating cell types that are distributed throughout the body. 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. 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. 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. 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 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. ![]() 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. Despite their therapeutic potential 2, our map of these surface interactions remains incomplete 3, 4. 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.
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