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

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.

STING Protein‐Based In Situ Vaccine Synergizes CD4+ T, CD8+ T, and NK Cells for Tumor Eradication

“…This resulted in effective suppression of the undesirable T reg within the TME while achieving ≈30% T H 1 polarization of CD4 + T cells in vivo (Figure 5G and Figure S9, Supporting Information). While we recognize the reported toxicity and impairment of cellular func-tion of T cells due to direct STING activation, [78][79][80] the overall role of CD4 + T cells in our treatment as well as in the BCG therapy [77] has been demonstrated to be indispensably beneficial. Future investigations on the mechanism of CD4 + T cell STING signaling might decouple the undesirable side effects from the benefits of T H 1-mediated anti-tumoral effects and thus provide important insight for effective drug delivery strategies.…”

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

“…[55,56] Furthermore, STING activation in T cells can lead to T cell death, which can impair the establishment of anti-tumour adaptive immune responses. [57,58] Importantly, downregulation of cGAS and/or STING has been reported in several cancers and has been proposed to serve as an immune escape strategy. [59,60] However, high expression of cGAS and/or STING has also been shown to predict poor outcome for cancer patients.…”

“…[ 55,56 ] Furthermore, STING activation in T cells can lead to T cell death, which can impair the establishment of anti‐tumour adaptive immune responses. [ 57,58 ]…”

The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

“…Characterized as an innate immune sensor, STING expression is, paradoxically, high in CD4 T cells 12,21 . Furthermore, STING activation kills mouse and human CD4 T cells ex vivo 22–24 . SAVI patients and mouse model had CD4 T cellpenia 12,24 .…”

“…Together, the absence of STING in mice does not alter T cell development or TCR signaling 22 . In humans, SAVI patients with constitutively activated STING have low CD4 T cell numbers 12 , and type I IFNs are dispensable for STING-mediated human CD4 T cell death 24 . Notably, SAVI patients (N154S or V155M) had similar counts of CD8 T and B cells 12 .…”