Leukocyte Chemotaxis and the Elusive Negative Signals that Make It Work

The recruitment of leukocytes to target locations in the body is central to both effective immune responses and pathological inflammation. Leukocytes use chemotaxis to find their way, following shallow gradients of attractants through complex tissue environments. To accomplish this feat, the cells adapt to external attractant concentrations, sense spatial differences in attractant levels across the cell, and establish a stable but steerable cell polarity to move persistently while navigating around obstacles. These dynamic behaviors are critical for effective chemotaxis, and they emerge from the molecular wiring of the underlying signaling and cytoskeletal components. Positive and negative feedback, as well as cross talk connections between cell front and rear components, play central roles. However, our understanding of these connections is still limited, especially regarding the inhibitory connections necessary for information processing and spatial organization. Here, we highlight recent progress and remaining challenges in uncovering the key components and their regulation that could explain dynamic features of chemotaxis and may suggest new therapeutic approaches.