Immune responses rely on the efficient movement of immune cells within the complex and geometrically unpredictable three-dimensional tissues that make up our bodies. Recent research by the Sixt group at the Institute of Science and Technology Austria (ISTA) unveils how immune cells use their cytoskeleton to exert forces on their surrounding environment to push their way through tissues. The findings were published in Nature Immunology.
"Eww; what, inside of me?" A common response when Patricia Reis-Rodrigues, a PhD student in the Sixt group at ISTA , reveals that dendritic cells—a type of immune cell—are constantly moving throughout our bodies. Dendritic cells can be found in the peripheral tissues, like the skin, where they scan for intruders such as bacteria or viruses. When they encounter such pathogens, dendritic cells get activated and migrate from the infection site to the lymph nodes, where they interact with T cells to start the fight against the infection.
Effective immune responses rely on the efficient and coordinated movement of dendritic cells throughout our body. However, navigating three-dimensional tissues can be complex and unpredictable, and cells need to make use of their organelles and cytoskeleton in different ways to overcome the obstacles that surround them.
Navigating through complex environments
In order to migrate through these intricate environments, dendritic cells rely on actin polymerization at their front to form an exploratory protrusion called lamellipodium that directs forward motion. At the same time, "cells can use their nucleus to probe their surroundings," Reis-Rodrigues explains, "to find and choose the most accessible paths."
But what happens when cells face constricted spaces that are too small to allow free passage? While fibroblasts (cells involved in tissue repair) or cancer cells often secrete proteolytic enzymes that digest their environment to make room, dendritic cells use a different technique. "If our dendritic cells did that, they would eat away too much of our tissue, which would be very bad. You would be quite holey," Reis-Rodrigues chuckles.
Reis-Rodrigues and colleagues' newest paper, which was just published in Nature Immunology, shows that, when confronted with tight spaces, dendritic cells assemble a distinct actin structure at the center of the cell body. This central actin structure can push the surrounding obstacles away, orthogonally to the direction of movement, generating space for the cells and helping them overcome even the tightest holes. The success of this strategy relies heavily on the coordination between these outward pushing forces at the center of the cell, and the forces at the front that form the lamellipodium and promote forward migration.
Unable to push, cells get trapped and entangled
"We were curious to know what would happen when cells are unable to exert or coordinate these forces", says Reis-Rodrigues. The researchers found that dendritic cells depleted of DOCK8 completely lacked the central actin structure and had severe defects while migrating in complex environments. Indeed, mutations in the Dock8 gene result in a rare and chronic immune disorder where affected individuals experience recurring viral infections and skin problems.
"There was no clear understanding of why a mutation in this gene would impact our cells so significantly and lead to the development of such severe symptoms in people," Reis-Rodrigues explains. The team demonstrated that unlike healthy immune cells, the inability of DOCK8 mutants to push outwards and open up narrow environments trapped the cell body in tight holes. The lack of the central actin structure also led to extensive uncontrolled protrusions at the front, elongating cells so much that they even fragmented and died.
The research reveals a new molecular mechanism used by cells migrating through the complex tissues of our bodies. It highlights the importance of an efficient coordination between the forward and outward protrusive forces to move forward and overcome physical obstacles without compromising cell integrity.
