What is it about?
In this study, scientists from the Leibniz Institute for Immunotherapy (LIT) in Regensburg (Germany) developed environment-sensing synthetic biosensors for murine and human regulatory T cells (Treg cells) that bind inflammatory molecules of the tumor necrosis factor (TNF) super family and, thereby, translate this inflammatory signal into a T cell receptor (TCR)-like activation program. Treg cell activation by these engineered receptors is therefore triggered in an environmental-dependent manner. The study provides a novel alternative strategy to engineer Treg cells for cellular therapy of inflammatory diseases in which the disease-driving antigens are unknown. As a proof-of-principle in vivo experiment, it was demonstrated that engineered inflammation-sensing Treg cells protect significantly better than Treg cells missing this biosensor against the development of graft versus-host disease.
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Why is it important?
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. In human autoimmune diseases, the implicated autoantigens, which could serve as potential targets for antigen specific CAR–Treg cells, are often unknown or vary strongly between individual patients. In addition, in many autoimmune and alloreactive diseases, multiple organs and tissues are affected without a uniform antigen that could be targeted by CAR–Treg cells. In contrast to this, the mediators of inflammation show a high redundancy as well as functional importance for the development of various inflammatory diseases, including autoimmunity and alloreactivity. Especially, cytokines of the tumor necrosis factor (TNF) superfamily are involved in many different inflammatory and autoimmune diseases. For example, therapeutic intervention with TNF receptor (TNFR) activation is an important treatment option for several inflammatory diseases. These considerations led LIT scientists Sebastian Bittner, Thomas Hehlgans and Markus Feuerer to develop a concept for engineered Treg cell therapy by generating artificial immune receptors (AIRs) that target these inflammatory mediators instead of tissue-specific antigens. In sum, LIT scientists provide a synthetic immune receptor concept for engineering Treg cells that are activated by the inflammatory environment, opening therapy options to address various diseases with (multiorgan) inflammation.
Perspectives
The new Artificial Immune Receptors (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. 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. 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. On this basis, we are now planning to design specific immune cell therapies using Treg cells engineered with AIRs.
Sebastian Bittner
Leibniz Institute for Immunotherapy, 93053 Regensburg, Germany
Read the Original
This page is a summary of: Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy, Proceedings of the National Academy of Sciences, September 2022, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2208436119.
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