Synthetic biosensors reprogram Treg cells to tame autoimmunity and chronic inflammation

An estimated 5-8 percent of the world’s population suffers from an autoimmune disease. Autoimmunity is a misdirected immune response against one’s own organism. This erroneous reaction is the consequence of a lack of tolerance of the immune system to the body’s own structures or an incorrect differentiation between potentially dangerous attackers such as bacteria, fungi, and viruses and the body’s own structures. One of the most important cellular checkpoints are regulatory T cells (Treg cells). They modulate the function of other immune cells and, thereby, prevent the development of autoimmune diseases.

Interestingly, research in recent years has demonstrated that Treg cells are suitable for therapeutic approaches against diseases such as rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease. In addition, the use of Treg cells in organ and stem cell transplantation can also reduce the rejection reaction to the transplant.

Scientists from the Division of Immunology at the Leibniz Institute for Immunotherapy (LIT) have now developed new types of synthetic biosensors, so-called artificial immune receptors (AIRs), which can be used to reprogram Treg cells into intelligent “smart” Tregs. The results of these studies have now been published by Dr. Sebastian Bittner, Prof. Dr. Thomas Hehlgans, and Prof. Dr. Markus Feuerer in the journal PNAS.

“AIRs allow Treg cells to detect and respond to inflamed tissue in their environment. Thus, different inflammatory molecules of the tumor necrosis factor superfamily are recognized by the synthetic biosensors, whereby the Treg cells start to exert their protective and regenerative effect directly in the inflamed tissue,” explains Sebastian Bittner. In preclinical models, the protective effect of these modified Treg cells has already been demonstrated to prevent lethal graft-versus-host disease, a severe side effect of allogeneic stem cell transplantation. “The molecular functionality of these biosensors has already been confirmed also in human Treg cells, demonstrating the translational feasibility of this technology” says Thomas Hehlgans.

These new biosensors could potentially be used for multiple medical indications, as they detect inflammatory mediators that are present in several autoimmune diseases, chronic inflammation, and transplantation complications. “Therefore, the therapeutic use of the modified Treg cells will be tested in further preclinical disease models, e.g., Crohn’s disease, an inflammatory bowel disease”, describes Markus Feuerer. On this basis, LIT scientists now plan to design specific immune cell therapies using Treg cells engineered with AIRs.

For more information, please visit the full article in the journal “PNAS”:

Sebastian Bittner, Brigitte Ruhland, Veronika Hofmann,  Lisa Schmidleithner, Kathrin Schambeck, Asmita Pant, Philipp Stüve, Michael Bernd Echtenacher, Matthias Edinger, Petra Hoffmann, Michael Rehli, Claudia Gebhard, Nicholas Strieder, Thomas Hehlgans, and Markus Feuerer. Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. PNAS Vol. 119 | No. 40, 2022

www.pnas.org/doi/10.1073/pnas.2208436119