Eomesodermin promotes interferon‐γ expression and binds to multiple conserved noncoding sequences across the <i>Ifng</i> locus in mouse thymoma cell lines

Fukuoka, Natsuki; Harada, Misuzu; Nishida, Ai; Ito, Yuko; Shiota, Hideki; Kataoka, Takao

doi:10.1111/gtc.12328

Cited by 11 publications

(16 citation statements)

References 60 publications

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“…Our data indicate that IFN-γ production by Tc REG is controlled by NF-κB signaling. Based on our data and published studies (52, 63, 64), we interpret these results to indicate that NF-κB contributes (or regulates) to the expression of T-bet and Eomes in Tc REG , which then leads to IFN-γ production (Fig. 5D).…”

Section: Discussionsupporting

confidence: 81%

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Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Shashkova

Trivedi

Cline-Smith

et al. 2016

The Journal of Immunology

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Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as antigen-presenting cells. Cross-presentation of antigens by osteoclasts leads to expression of CD25 and FoxP3, markers of regulatory T-cells in the CD8 T-cells. Osteoclast-induced FoxP3+ CD8 T-cells (OC-iTcREG) suppress priming of CD4 and CD8 T-cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. Here we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet and Eomes production by TcREG. Furthermore, we show using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoter. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand (RANKL) needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ−/− T-cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose RANKL. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish important role for IFN-γ in TcREG-mediated protection from bone loss.

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Section: Discussionsupporting

confidence: 81%

“…It has been reported previously that T-bet and Eomes bind to distal conserved non-coding sequences (CNS) to regulate histone modification and expression of IFN-γ gene (50–52). Consistent with these results, we found that in Tc REG cells T-bet and Eomes bind to CNS located at −22K and −34K from IFN-γ gene transcription start (Fig.…”

Section: Resultsmentioning

confidence: 99%

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Shashkova

Trivedi

Cline-Smith

et al. 2016

The Journal of Immunology

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“…We then transfected EL-4 mouse lymphoma cells with a luciferase reporter system containing a 2 kb Tox promoter region and determined whether T-bet repressed Tox transcription directly. EL-4 cells lack endogenous expression of T-bet and Eomes (Fukuoka et al, 2016), and retrovirally delivered T-bet but not Eomes reduced the activity of the Tox reporter construct by 50%–60% (Figure 3F). Furthermore, we analyzed LCMV-OVA-primed OT-1 cells by T-bet chromatin immunoprecipitation analysis followed by PCR (ChIP-PCR) of various Tox promoter regions.…”

Section: Resultsmentioning

confidence: 99%

Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells

et al. 2018

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Infections are thought to trigger CD8 cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.

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“…DNA was purified by Qiagen PCR purification kit and used as template for PCR amplification with specific primers flanking the T-bet binding sites in CNS enhancer regions of the Ifng locus as defined previously (18, 19). The primers (20) used are listed below:…”

Section: Methodsmentioning

confidence: 99%

Egr2 and 3 Inhibit T-bet–Mediated IFN-γ Production in T Cells

Singh

Miao

Symonds

et al. 2017

The Journal of Immunology

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T-bet is important for differentiation of cytotoxic CD8 and Th1 CD4 T cells. We have discovered that Egr2 and 3 are potent inhibitors of T-bet function in CD4 and CD8 effector T cells. Egr2 and 3 were essential to suppress Th1 differentiation in Th2 and Th17 conditions in vitro and also to control IFN-γ–producing CD4 and CD8 T cells in response to virus infection. Together with Egr2 and 3, T-bet is induced in naive T cells by Ag stimulation, but Egr2 and 3 expression was inhibited by Th1–inducing cytokines. We found that Egr2 and 3 physically interact with the T-box domain of T-bet, blocking T-bet DNA binding and inhibiting T-bet–mediated production of IFN-γ. Thus, Egr2 and 3 are antagonists of T-bet function in effector T cells and are important for the control of inflammatory responses of T cells.

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Eomesodermin promotes interferon‐γ expression and binds to multiple conserved noncoding sequences across the Ifng locus in mouse thymoma cell lines

Cited by 11 publications

References 60 publications

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells

Egr2 and 3 Inhibit T-bet–Mediated IFN-γ Production in T Cells

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