summary: Researchers have made significant progress in understanding how immune cells move around within the body. Contrary to previous belief, these cells not only respond to directional signals, but also form their own pathways.
The study provides insights into the ability of stem cells to modulate chemokine concentrations and direct their movement. This knowledge can improve our immune response in fighting disease.
- Dendritic cells (DCs) play a pivotal role in the immune response, acting as messengers and scanning tissues for invaders.
- Rather than simply following chemical gradients, DCs modify these concentrations by actively consuming them, aiding their movement.
- The motility and response of DCs depends not only on individual interactions, but also on the density of the cell population.
When fighting disease, our immune cells need to get to their target quickly. Researchers at the Institute of Science and Technology Austria (ISTA) have now discovered that immune cells actively generate their own guidance system to navigate through complex environments. This challenges previous notions about these movements.
The researchers’ findings were published in the journal Immunologyand advance our knowledge of the immune system and provide potential new approaches to improving the human immune response.
Immune threats such as germs or toxins can arise everywhere within the human body. Fortunately, the immune system – our own protective shield – has its own intricate ways of dealing with these threats.
For example, a critical aspect of our immune response involves the coordinated collective movement of immune cells during infection and inflammation. But how do our immune cells know which way to go?
This question was addressed by a group of scientists from the Sixt group and the Hanizou group at the Institute of Science and Technology Austria (ISTA). In their study, the researchers highlight the ability of immune cells to migrate collectively across complex environments.
Stem cells – messengers
Dendritic cells (DCs) are one of the major players in our immune response. It acts as a messenger between the innate response – the body’s first reaction to an invader, and the adaptive response – a delayed reaction that targets very specific germs and creates memories to fight off future infections. Like detectives, data centers scan tissue for hackers.
Once they locate an infection, they are activated and immediately travel to the lymph nodes, where they deliver the battle plan and begin the next steps in the chain.
Its migration towards the lymph nodes is directed by chemokines – small signaling proteins released from the lymph nodes – which create a gradient.
In the past, it was thought that stem cells and other immune cells react to this external gradient, moving towards a higher concentration. However, new research conducted at ISTA is now challenging this notion.
One future – two jobs
The scientists took a closer look at the receptor, which is a surface structure found in activated DCs called ‘CCR7’. CCR7’s primary function is to bind to a lymph node-specific molecule (CCL19), which triggers the next steps of the immune response.
“We found that CCR7 not only senses CCL19, but also actively contributes to shaping the distribution of chemokine concentrations,” explains Jona Alanko, a former postdoctoral researcher from Michael Sixt’s lab.
Using various experimental techniques, they demonstrated that when DCs migrate, they take up and internalize chemokines via the CCR7 receptor, leading to a local depletion of chemokine concentration.
With fewer signaling molecules around, they move to higher chemokine concentrations. This dual function allows immune cells to generate their own guidance signals to more effectively regulate their collective migration.
Movement depends on the number of cells
To quantitatively understand this mechanism at the multicellular level, Alanko and colleagues collaborated with theoretical physicists Edward Hanizou and Mehmet Can Okkar, also at ISTA. With their expertise in cell movement and dynamics, they created computer simulations that were able to reproduce Alanko’s experiments.
Through these simulations, the scientists predicted that the movement of stem cells would depend not only on their individual responses to chemokines but also on the density of the cell population.
This was a simple but not trivial prediction; “The more cells there are, the greater the gradient they generate, which really highlights the collective nature of this phenomenon,” says Kan Okkar.
In addition, the researchers found that T cells — specific immune cells that destroy harmful germs — also take advantage of this dynamic interaction to enhance their directional motility. The physicist continues, “We are keen to learn more about this new interaction principle between populations of cells with ongoing projects.”
Boosting the immune response
These discoveries are a step in a new direction for how cells move inside our bodies. Contrary to what was previously thought, immune cells not only respond to chemokines, they also play an active role in shaping their own environment by consuming these chemical signals. This dynamic regulation of signaling signals provides an elegant strategy for directing its movement and that of other immune cells.
This research has important implications for our understanding of how immune responses are orchestrated within the body. By uncovering these mechanisms, scientists can design new strategies to enhance the recruitment of immune cells to specific sites, such as cancer cells or areas of infection.
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“CCR7 acts as a sensor and sink for CCL19 to coordinate collective leukocyte migrationPosted by Jonah Alanko et al. Immunology
CCR7 acts as a sensor and sink for CCL19 to coordinate collective leukocyte migration
Immune responses depend on the rapid and coordinated migration of leukocytes. While it is well established that single cell migration is often guided by gradients of chemicals and other chemical attractants, it remains poorly understood how these gradients are generated, maintained, and modified.
By combining experimental data and theory of leukocyte chemotaxis guided by the G protein receptor (GPCR) CCR7, we demonstrated that in addition to its role as a sensory receptor directing migration, CCR7 also functions as a generator and modulator of chemical gradients. .
Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) actively internalize the receptor and ligand as part of a basic GPCR desensitization response.
We have shown that CCR7 internalization also acts as an efficient sink of the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine.
This mechanism drives complex mass migration patterns, enabling DCs to establish or sharpen chemical gradients.
We also show that these self-generated gradients can maintain long-range orientation of DCs, adapt collective migration patterns to environment size and geometry, and provide a steering signal to other companion cells.
Such a dual role of CCR7 as a GPCR that senses and consumes its ligand could provide a new method for cellular self-regulation.
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