Dendritic cells (DCs) travel great distances to transport antigens from peripheral tissues to lymph nodes. Chemotactic gradients control immune cell trafficking, although whether DCs can alter these gradients is unclear.
Using a combination of live cell imaging and mathematical modeling, scientists, in a new study, identified a dual role for the G protein–coupled receptor (GPCR) CCR7 in controlling DC migration.
According to new research from the Institute of Science and Technology Austria (ISTA), immune cells actively build their navigation system to travel across complex settings. The study could enhance our knowledge of the immune system and offer potential new approaches to improve human immune response.
Scientists from the Sixt group and the Hannezo group at the Institute of Science and Technology Austria (ISTA) shed light on the immune cells’ ability to migrate through complex environments collectively.
One of the major participants in our immune response is dendritic cells (DCs). They link the adaptive response, a delayed response that targets particular bacteria and builds memories to fight off future infections, and the innate response, which is the body’s initial response to an invasion. DCs search tissues for intrusions like detectives. They are triggered when they find an infection site and travel immediately to the lymph nodes, where they transfer the combat strategy and start the subsequent phases in the cascade.
Chemokines are tiny signaling proteins produced by lymph nodes and create a gradient, directing their migration toward the lymph nodes. It was initially thought that immune cells such as DCs respond to the progression of this extrinsic gradient towards a larger concentration. However, a recent ISTA study casts doubt on this assumption.
The surface feature known as “CCR7” that is present on activated DCs was closely examined by scientists. The crucial role of CCR7 is to bind to the CCL19, a lymph node-specific molecule, which sets off the subsequent stages of the immune response.
Jonna Alanko, a former postdoc from the lab of Michael Sixt, explains, “We found that CCR7 not only senses CCL19 but also actively contributes to shaping the distribution of chemokine concentrations.”
They used different experimental techniques and found that as DCs migrate, they take up and internalize chemokines via the CCR7 receptor, resulting in local depletion of chemokine concentration. They progress into higher chemokine concentrations because there are fewer signaling molecules present. Immune cells can produce their guidance cues thanks to their dual function, which improves the coordination of their group migration.
Together with theoretical physicists Edouard Hannezo and Mehmet Can Ucar from ISTA, Alanko, and colleagues developed a quantitative understanding of this mechanism at the multicellular scale. They developed computer simulations that could replicate Alanko’s studies using their cell dynamics and mobility knowledge. Using these simulations, scientists hypothesized that the migration of dendritic cells is influenced by the cell population’s density and individual responses to chemokines.
Can Ucar said, “This was a simple but nontrivial prediction; the more cells there are, the sharper the gradient they generate—it really highlights the collective nature of this phenomenon!”
Scientists also found that T-cells—specific immune cells that destroy harmful germs—benefit from this dynamic interplay to enhance their directional movement.
The physicist said, “We are eager to learn more about this novel interaction principle between cell populations with an ongoing project.”
The findings mark a turning point in our understanding of how cells migrate within our bodies. Contrary to what was previously thought, immune cells actively regulate their environments by eating chemokines and responding to them. The dynamic modulation of signaling signals provides an elegant method for directing their mobility and the movement of other immune cells.
Our understanding of how immune responses are coordinated throughout the body will be greatly affected by the findings of this study. By figuring out these systems, researchers can develop fresh methods for boosting immune cell recruitment to particular locations, including infected or tumorous cells.
Journal Reference:
- J. Alanko, M. C. Ucar, N. Canigova, J. Stopp, J. Schwarz, J. Merrin, E. Hannezo & M. Sixt. 2023. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science Immunology. DOI: 10.1126/sciimmunol.adc9584