STING agonism turns human T cells into interferon‐producing cells but impedes their functionality

Kuhl, Niklas ; Linder, Andreas ; Philipp, Nora ; Nixdorf, Daniel ; Fischer, Hannah ; Veth, Simon; Kuut, Gunnar; Xu, Teng Teng ; Theurich, Sebastian ; Carell, Thomas; Subklewe, Marion und Hornung, Veit (2023): STING agonism turns human T cells into interferon‐producing cells but impedes their functionality. In: EMBO reports, Bd. 24, Nr. 3

Abstract

The cGAS‐STING (cyclic GMP‐AMP synthase‐stimulator of interferon genes) axis is the predominant DNA sensing system in cells of the innate immune system. However, human T cells also express high levels of STING, while its role and physiological trigger remain largely unknown. Here, we show that the cGAS‐STING pathway is indeed functional in human primary T cells. In the presence of a TCR‐engaging signal, both cGAS and STING activation switches T cells into type I interferon‐producing cells. However, T cell function is severely compromised following STING activation, as evidenced by increased cell death, decreased proliferation, and impaired metabolism. Interestingly, these different phenotypes bifurcate at the level of STING. While antiviral immunity and cell death require the transcription factor interferon regulatory factor 3 (IRF3), decreased proliferation is mediated by STING independently of IRF3. In summary, we demonstrate that human T cells possess a functional cGAS‐STING signaling pathway that can contribute to antiviral immunity. However, regardless of its potential antiviral role, the activation of the cGAS‐STING pathway negatively affects T cell function at multiple levels. Taken together, these results could help inform the future development of cGAS‐STING‐targeted immunotherapies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1469-221X
• Sprache: Englisch