Global coordination of protrusive forces in migrating immune cells

Efficient immune responses rely on the capacity of leukocytes to traverse diverse and complex tissues. To meet such changing environmental conditions, leukocytes usually adopt an amoeboid configuration, utilizing their forward-positioned nucleus as a probe to identify and follow the path of least resistance among pre-existing pores. We show that in dense environments, where even the largest pores preclude free passage, leukocytes switch polarity and position their nucleus behind centrosome and organelles. In this mesenchymal configuration, local compression of the cell body triggers assembly of a central F-actin pool, located between cell front and nucleus. Central actin pushes outward to transiently dilate a path for organelles and nucleus. Pools of central and front actin are tightly coupled and experimental depletion of the central pool enhances actin accumulation and protrusion formation at the cell front. Although this shifted balance speeds up cells in permissive environments, migration in restrictive environments is impaired, as the unleashed leading edge dissociates from the trapped cell body. Our findings establish an actin regulatory loop that balances path dilation with advancement of the leading edge to maintain cellular coherence.