Connection interrupted? How regulatory cells selectively tune down immune responses.

Our immune system constantly protects us from threats originating from both the outside and inside of our bodies. One example of internal threats are autoreactive immune cells, which attack our own tissues. Like powerful machines, the immune system requires regulation. There are checkpoints in every immune response and different immune cells must effectively communicate to orchestrate a balanced, beneficial response.

Regulatory T cells (Tregs) are crucial immune cells whose role is to control immune responses by suppressing the activity of other immune cells. A recent study demonstrated a novel mechanism in which Tregs inhibit other T cells by preventing their communication with dendritic cells. These findings may underlie Treg-mediated suppression of autoimmune diseases.

Communication between immune cells

Dendritic cells are sentinels of the immune system. They sample our tissues in search for antigens. Antigens are components of microorganisms that trigger an immune response. However, not all cells are able to “see” antigens on their own; they need help from dendritic cells. Once dendritic cells identify a stimulus, they take it up and process the antigens. Next, these antigens are loaded into a special receptor on the outer surface of the dendritic cell. During these steps, dendritic cells travel to the lymph nodes where they communicate their “findings” to T cells.  

Once in the lymph node, the dendritic cells start looking for a naïve T cell. Naïve T cells are immune cells that have never participated in an immune response. They are strategically placed to interact with the antigen-receptor complex on the surface of dendritic cells. T cells themselves have a receptor which recognizes the complex, but only a few naïve T cells will recognize the specific antigen-receptor introduced by the dendritic cell. This process is called antigen presentation and it ensures that the immune response elicited is specific for the threat sensed by the dendritic cell.

Once the antigen is presented to the naïve T cells, they develop into different types of T cells. Effector T cells coordinate the immune response by producing mediators which dictate the function of other immune cells. In addition to effector T cells, Tregs are also formed during immune responses. Tregs suppress the function of nearby effector T cells through physical interactions as well as secretion of inhibitory mediators. These mechanisms fall under the umbrella of what immunologists call bystander suppression, a phenomenon characterized by inhibition of immune cells in a given microenvironment, regardless of their specificity.  

Tregs prevent the communication between dendritic cells and naïve T cells of the same specificity

In a recent report, a novel mechanism of immune suppression exerted by Tregs was discovered. Different from bystander suppression, this mechanism mediates specific suppression of effector T cells meaning that Tregs only affect naïve T cells of the same specificity. They achieve this by preventing communication with dendritic cells.

The authors first observed that in the presence of both Tregs and naïve T cells of the same specificity, dendritic cells preferentially interact with the Tregs. However, if the naïve T cells are specific for a different antigen-receptor complex, the Tregs do not interfere with the interactions between the dendritic and the naïve T cells anymore. From these observations, we appreciate that Tregs inhibit naïve T cells in a specific manner, but how are they doing it? Is this a mere competition between Tregs and naïve T cells, or are the Tregs changing something in the dendritic cell?

To further understand this process, the authors allowed dendritic cells and Tregs to interact. A few hours later, the Tregs were removed and replaced by naïve T cells of the same specificity. The interactions between the naïve T cells and the dendritic cells were still impaired, even in the absence of Tregs. This means that it is not simply a “race” between Tregs and naïve T cells, but rather that Tregs affect the function of the dendritic cells. In fact, when the dendritic cells were re-exposed to the specific antigen after the removal of the Tregs, their ability to interact with the naïve T cells was restored.  

This led the authors to suspect that the Tregs were preventing the communication between naïve T cells and dendritic cells by reducing the number of antigen-receptor complexes on the surface of dendritic cells. Indeed, these complexes were depleted from dendritic cells upon interactions with Tregs through a process in which Tregs “picked up” the antigen-receptor complexes from the dendritic cells. Tregs were only able to pick up the receptors complexed with the antigen they were specific for. If the dendritic cell presented a second antigen in another receptor, the complex was not removed by the Treg.

How can our body harness this mechanism? Tregs are important for controlling immune responses, including the ones elicited against our own tissues. Our immune system is not perfect and sometimes we produce autoreactive naïve T cells, which recognize components of our body as threats, if they are introduced by a dendritic cell. Some Tregs are also specific for these components. Hence, this could be a crucial mechanism by which Tregs protect our body against autoimmunity. By preventing dendritic cells from communicating with autoreactive naïve T cells, our immune system has found a way to specifically stop these damaging responses without impairing the beneficial ones.

ImmunoBites Mechanism Figure jpg


Amanda Zucoloto (author) is a PhD student at the University of Calgary Cumming School of Medicine, Canada. Her research focuses on the immune response during bacterial sepsis.

Mia Koegler (illustrator) is an MD/MSc student at the University of Calgary Cumming School of Medicine, Canada. Her research focuses on the functional interplay between the microbiota, T cells, and immunoglobulins.

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