Communication through autoattractants can enhance and limit collective migration of immune cells

Abstract Many eukaryotic cells produce attractant molecules to which they themselves are also attracted. For example, neutrophils produce leukotriene B4 while swarming. These autoattractants create a secondary signalling layer that coordinates collective cell behaviour. The principles by which autoattractants shape migration, however, remain poorly understood. Here we use a hybrid agent-based computational model to dissect the effects of autoattractants on the collective chemotaxis of immune cells. We find that autoattractant signals strongly enhance cells’ responses to primary attractant, but only if the autoattractant is sufficiently short-lived: at longer lifetimes, accumulation degrades the directional information cells can extract. The overall effect of autoattractants therefore depends crucially on the balance between production and efficient removal — whether through cellular uptake, enzymatic breakdown, or inherent chemical instability. Optimal lifetimes exist, determined by cell speed and attractant diffusion, yet remarkably independent of cell density and primary attractant concentration. Autoattractants whose removal is governed by inherent instability rather than direct cellular breakdown coordinate migration less efficiently, but work more robustly across different environments. In the absence of cell-mediated breakdown, the model further reveals a characteristic optimal cell–cell distance: too little communication leaves cells uncoordinated, while excessive signalling drives them into slow-moving aggregates. Strikingly, the conditions that produce the most efficient chemotaxis lie close to those that trigger aggregation, suggesting that many autoattractant systems operate near a critical boundary that can be tuned by evolution either to disperse cells or to bring them together. Author Summary Immune cells must travel through the body to reach sites of injury, infection, and developing tissue. They are guided by chemical signals. Many immune cells, such as neutrophils gathering at wounds and microglia in the brain, also release their own signals that attract others of the same kind. We call these ’autoattractants’. In effect, the cells tell each other where to go. This communication helps coordinate group movement, but little is known about how it works. We built a computer simulation of migrating immune cells to explore how autoattractants shape their collective behaviour. We find that autoattractants must be short-lived to be useful: when autoattractant accumulates, it obscures any sense of direction. Signals that cells actively break down, or that decay on their own, carry clear directional information. With signals that decay on their own, a delicate balance emerges: just enough cooperation leads to the most efficient coordinated migration, while a little too much causes cells to clump together instead of moving forward. Our work suggests that many more cell types may use this communication than we know, and that the same system can be tuned by evolution to spread cells out or to gather them together.