STING agonism turns human T cells into interferon‐producing cells but impedes their functionality. (27th January 2023)

• Record Type: Journal Article
• Authors: Kuhl, Niklas; Linder, Andreas; Philipp, Nora; Nixdorf, Daniel; Fischer, Hannah; Veth, Simon; Kuut, Gunnar; Xu, Teng Teng; Theurich, Sebastian; Carell, Thomas; Subklewe, Marion; Hornung, Veit
• Is Part Of: EMBO reports. Volume 24:Number 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-27
• Subjects: antiviral immune response -- cGAS -- STING -- T cell -- T cell dysfunction; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202255536
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: In primary human T cells, the activation of the innate sensor STING leads to antiviral cytokine release. However, T cell functionality is reduced upon STING activation through increased apoptosis, impaired proliferation, and compromised metabolism. Innate sensors cGAS and STING are operational in human T cells. STING activation induces antiviral cytokine production in TCR‐activated human T cells. TCR activation strongly boosts STING activation and antiviral gene expression. STING activation in human T cells induces apoptosis and impairs proliferation and metabolism. Abstract : In primary human T cells, the activation of the innate sensor STING leads to antiviral cytokine release. However, T cell functionality is reduced upon STING activation through increased apoptosis, impaired proliferation, and compromised metabolism.