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 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.

人体免疫系统由分布在全身循环的细胞网络组成，这些细胞必须动态地形成物理关联，并利用其细胞表面蛋白质组¹之间的相互作用进行通信。尽管它们具有治疗潜力²，但我们对这些表面相互作用的图谱仍然不完整^3,4. 在这里，我们使用高通量表面受体筛选方法，系统地绘制了跨重组文库的直接蛋白质相互作用，该文库包含在人类白细胞上可检测到的大多数表面蛋白质。我们独立验证并确定了每一种新型相互作用的生物物理参数，从而对连接人类免疫细胞的受体线路进行了高度可信和定量的观察。通过将我们的相互作用组与表达数据相结合，我们确定了免疫相互作用动力学的趋势，并构建了一个简化数学模型，从基本原理预测细胞连通性。我们还开发了一个交互式多组织单细胞图谱，可以推断全身免疫相互作用，揭示多细胞网络中新交互和枢纽的潜在功能环境。最后，我们将人类白细胞的靶向蛋白质刺激与多重高内涵显微镜相结合，将我们的受体相互作用与功能作用联系起来，在调节免疫反应和维持细胞间关联的正常模式方面。总之，我们的工作为人类免疫系统的细胞间布线提供了一个系统的视角，从免疫细胞连接的系统级原理延伸到个体受体的机械表征，这可能为治疗干预提供机会。在调节免疫反应和维持细胞间结合的正常模式方面。总之，我们的工作为人类免疫系统的细胞间布线提供了一个系统的视角，从免疫细胞连接的系统级原理延伸到个体受体的机械表征，这可能为治疗干预提供机会。在调节免疫反应和维持细胞间结合的正常模式方面。总之，我们的工作为人类免疫系统的细胞间布线提供了一个系统的视角，从免疫细胞连接的系统级原理延伸到个体受体的机械表征，这可能为治疗干预提供机会。