Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy

Author:

Bittner Sebastian12,Ruhland Brigitte12,Hofmann Veronika12,Schmidleithner Lisa12,Schambeck Kathrin12,Pant Asmita12,Stüve Philipp12,Delacher Michael3ORCID,Echtenacher Bernd12,Edinger Matthias14,Hoffmann Petra14,Rehli Michael14ORCID,Gebhard Claudia1,Strieder Nicholas1,Hehlgans Thomas12,Feuerer Markus12

Affiliation:

1. Leibniz Institute for Immunotherapy, 93053 Regensburg, Germany

2. Chair for Immunology, Universität Regensburg, 93053 Regensburg, Germany

3. Institute of Immunology, Universitätsmedizin Mainz, 55131 Mainz, Germany

4. Department of Internal Medicine III, Universitätsklinikum Regensburg, 93053 Regensburg, Germany

Abstract

Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells. AIRs consist of three domains: (a) extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, (b) intracellular costimulatory signaling domain of CD28, and (c) T cell receptor signaling domain of CD3-ζ chain. These AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-ζ chain–dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNFα, and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR–Treg cells. In a graft-versus-host disease model, Treg cells expressing lymphotoxin β receptor–AIR, which can be activated by the ligand LIGHT, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. Engineering Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell–based therapy approach for a broad range of inflammation-driven diseases.

Funder

EC | European Research Council

Deutsche Forschungsgemeinschaft

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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