The Brakes of the Immune System – How Regulatory T-Cells are Controlled

A successful activation of the immune system is of critical importance to the body in order to fight off infections and cancer. But it is just as important that the immune system is brought back to its normal state after its work is done, otherwise autoimmune diseases can result. Regulatory T cells (Tregs) are indispensable for this process because they are the brakes of the immune system. Tregs prevent immune cells from being spontaneously activated when there is no infection and they deescalate the immune system after a successful immune response. But thus far, little is known about how the Tregs themselves are regulated. Researchers from the Institute of Molecular and Clinical Immunology of the Otto-von-Guericke University (OvGU) Magdeburg and from the Helmholtz Centre for Infection Research have now deeply investigated this topic. They determined that Tregs multiply faster than conventional T cells, but also die more often. They live life in the fast lane.

Controlled cell death, so-called apoptosis, is a mechanism that the body often uses to precisely regulate the amount of a specific type of cell. This process is controlled through molecules on the surface of the cells, which read signals from the surroundings, pass these signals on to the inner cell and trigger a signal cascade that ultimately results in the death of the cell. While searching for the molecules that cause the large-scale cell death of Tregs, the researchers found that Tregs express the same amount of the death receptor CD95 as conventional T cells, but that they express less of the inhibitor c-FLIP on the inside. The brakes of the immune system are thus less able to prevent cell death through death receptors. In order to prove this, the scientists genetically deactivated c-FLIP in the Tregs of mice. This resulted in the animals having almost no Tregs, which resulted in an overreaction of the immune system and a fatal autoimmune disease, which was similar to IPEX Syndrome (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked) in humans.

Prof. Dr. Ingo Schmitz, the last author of the study, talked about the meaning of this result: “From this research, we have learned that c-FLIP is a highly interesting potential target of medication because manipulating c-FLIP activity with medication could be helpful against various diseases. A c-FLIP activator could allow Treg cells to live longer and prevent autoimmune diseases. On the other hand, a specific blockade of c-FLIP in Tregs could also be interesting for tumor disease because tumors often create an immunosuppressive environment by attracting Tregs and therefore evade the immune response. “ Researchers will search for medicines that influence the activity of c-FLIP in further studies.

Prof. Schmitz’s group is part of the Health Campus Immunology, Infectiology and Inflammation (GC-I³) of the OvGU. With the motto “Understand Inflammation – Cure Disease”, the GC-I³ has dedicated itself to understand, prevent and heal inflammation processes that play a role in the emergence and progression of many important, common diseases.

Original Publication: Plaza-Sirvent C, Schuster M, Neumann Y, Heise U, Pils MC, Schulze-Osthoff K, Schmitz I. c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity. Cell Rep. 2017 Jan 3;18(1):12-22.

Photo: Prof. Ingo Schmitz and Dr. Carlos Plaza-Sirvent, the first author of the study (private)