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

Bittner S, Ruhland B, Hofmann V, Schmidleithner L, Schambeck K, Pant A, Stüve P, Delacher M, Echtenacher B, Edinger M, Hoffmann P, Rehli M, Gebhard C, Strieder N, Hehlgans T, Feuerer M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 119

Article Number: e2208436119

Journal Issue: 40

DOI: 10.1073/pnas.2208436119

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.

Involved external institutions

Leibniz-Institut für Immuntherapie (LIT) / Leibniz Institute for Immunotherapy DE Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE)

How to cite

APA:

Bittner, S., Ruhland, B., Hofmann, V., Schmidleithner, L., Schambeck, K., Pant, A.,... Feuerer, M. (2022). Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Proceedings of the National Academy of Sciences of the United States of America, 119(40). https://dx.doi.org/10.1073/pnas.2208436119

MLA:

Bittner, Sebastian, et al. "Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy." Proceedings of the National Academy of Sciences of the United States of America 119.40 (2022).

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