Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation

Fueyo-González, Francisco; McGinty, Mitchell T.; Ningoo, Mehek; Anderson, Lisa R.; Cantarelli, Chiara; Angeletti, Andrea; Demir, Markus; Llaudo, Ines; Purroy, Carolina; Marjanović, Nada; Héja, Dávid; Sealfon, Stuart C.; Heeger, Peter S.; Cravedi, Paolo; Fribourg, Miguel

doi:10.1016/j.immuni.2022.01.011

Cited by 20 publications

(17 citation statements)

References 90 publications

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“… 36 Moreover, one recent study pointed out that exogenous INF-β could directly induce Treg from naïve CD4 + T cells by STAT1-dependent and P300-dependent FOXP3 acetylation in a Treg cell-dependent murine transplant model. 37 Together, our results suggest that STING in T cells functions to induce iTreg generation through TBK1 and IRF3 but works independently of IFN-β. In addition, the type I IFN-independent activity of STING is usually linked to antiproliferation and cell death in T cells by activation of NF-κB signaling and autophagy, and it is reported that the C-terminal domain of STING activates NF-κB to inhibit T cell proliferation.…”

Section: Discussionsupporting

confidence: 52%

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer

Zhang

et al. 2022

J Immunother Cancer

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BackgroundStimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments.MethodsBlood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture.ResultsIncreased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion.ConclusionsThese findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

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Section: Discussionsupporting

confidence: 52%

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer

Zhang

et al. 2022

J Immunother Cancer

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“…For example, YY1 plays a major role in the pathological mechanisms of RA by controlling the pathology of Th17 cells through binding to the promoter region of transcription factor T-bet and interacting with T-bet protein (16). Regulatory T cells are vital to maintain immune homeostasis, whose differentiation and function are regulated by an important transcription factor named Foxp3 (23). In a dextran sulfate-induced colitis model, YY1 increased regulatory T cells, reduced Foxp3 expression, and inhibit their suppressive function in immunity reaction (22).…”

Section: Discussionmentioning

confidence: 99%

The novel role of Yin Yang 1 in the acute rejection of liver allografts by activating dendritic cells

Chen

Wang

Liping

et al. 2023

Preprint

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Acute rejection that causes liver transplant dysfunction is the most common cause of mortality following liver transplantation. The potential role of Yin Yang 1 (YY1), a widely expressed zinc finger DNA-binding transcription factor, in acute rejection of liver allografts remains unknown. Here, we evaluated the effects and mechanisms of YY1 in an acute rejection using major histocompatibility complex (MHC) class II-mismatched rat liver transplantation model. On days 5 and 10 after liver transplantation, allografts showed elevated expression of YY1 in infiltrating inflammatory cells around the central vein of recipient livers accompanied by elevated levels of serum transaminase and proinflammatory cytokines. In vitro analysis showed that YY1-overexpressing DCs had higher expression of CD80, CD86, and MHC class II compared with the control group. Additionally, YY1-overexpressing DCs triggered naïve CD4+ T cells to produce high levels of intracellular cytokines IL-17 and TNF-γ. These results suggest that YY1 activates DCs and participates in the pathogenesis of acute rejection by polarizing naïve T cells to the inflammatory phenotype, making YY1 a candidate therapeutic target to avoid acute rejection after liver transplantation.

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“…The inhibitory effect of TGR5 on IFN-β expression by cAMPPKA is also reflected by the downregulation of the IFN-stimulated genes MxA and PKR in human macrophages 72 . IFN and T cells have intricate relationships and studies have shown that IFN-β increases the induction of Treg cells 73 . This suggested that the activation of TGR5 regulates the expression of interferon in macrophages.…”

Section: Tgr5mentioning

confidence: 99%

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment

Zhang

Gao

Yang

et al. 2023

Preprint

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According to reports, gut microbiota and metabolites regulate intestinal immune microenvironment. In recent years, an increasing number of studies reported that bile acids (BAs) of intestinal flora origin affects T helper cells and Treg cells. Th17 cells play a pro-inflammatory role and Treg cells usually act an immunosuppressive role. In this review, we emphatically summarized the influence and corresponding mechanism of different configurations of the LCA and DCA on intestinal Th17 cells, Treg cells and intestinal immune microenvironment. The regulation of BAs receptors G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune cells and intestinal environment are elaborated. Furthermore, the potential clinical applications above were also concluded in three aspects. These above will help researchers better understand the effects of gut flora on the intestinal immune microenvironment via BAs and contribute to the development of new targeted drugs.

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Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation

Cited by 20 publications

References 90 publications

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer

The novel role of Yin Yang 1 in the acute rejection of liver allografts by activating dendritic cells

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment

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