Tle4 Regulates Epigenetic Silencing of Gamma Interferon Expression during Effector T Helper Cell Tolerance

Bandyopadhyay, Souvik; Valdor, Rut; Macian, Fernando

doi:10.1128/mcb.00902-13

Cited by 11 publications

(9 citation statements)

References 61 publications

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“…However, Hrd1-mediated p27 Kip1 ubiquitination is unlikely to be the only molecular mechanism underlying Hrd1 function in CD4 differentiation because further deletion of p27 kip1 in Hrd1 cKO T cells failed to rescue the production of IL-2 and differentiation of Th1, Th17 and Treg. We recently discovered that Hrd1 is an E3 ubiquitin ligase of Blimp1, a transcriptional suppressor known to inhibit IL-2 production and Th1/Th17 differentiation 37 38 39 , raising the possibility that Hrd1 enhances IL-2 production and the differentiation of Th1 and Th17 by CD4 T cells 20 . Therefore, Hrd1-mediated Blimp1 ubiquitination and degradation to increase IL-2 production could be another possible molecular mechanism by which Hrd1 modulates CD4 T-cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

Xu¹,

Zhao²,

Qiu

et al. 2016

Nat Commun

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Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27kip1, and deletion of p27kip1 in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4+ T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

Xu¹,

Zhao²,

Qiu

et al. 2016

Nat Commun

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“…For example, TLE4 is a co-repressor that binds with a number of DNA binding proteins leading to the recruitment of repressor elements. One repressor function of TLE4 is the inhibition of IFNγ through epigenetic mechanisms in Th2 cells in order to maintain Th2 identity [ 48 ]. TLE4 also alters PAX5, a B cell master regulator, from a transcriptional activator to a repressor [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Methylene-tetrahydrofolate reductase contributes to allergic airway disease

et al. 2018

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RationaleEnvironmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors) in modifying allergic airway disease.ObjectivesWe hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr) activity would reduce the allergic airway disease phenotype through epigenetic mechanisms.MethodsAllergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM) exposure. Airway inflammation and airway hyperresponsiveness (AHR) were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine.Measurements and main resultsLoss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations.ConclusionCollectively, these findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification. Further investigation into the mechanisms that drive this observation is warranted.

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“…Notch signaling was suggested as a possible way to control the IFNγ production by human ILC2s [ 85 ] as they expressed TLE4, one Notch pathway related co-repressor which has been shown to repress IFN-γ expression through epigenetic regulation [ 86 ].…”

Section: Regulation Of Ilc Functions By the Notch Signaling Pathwaymentioning

confidence: 99%

The Notch signaling pathway involvement in innate lymphoid cell biology

Golub

2021

Biomedical Journal

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The role of Notch in the immune system was first described in the late 90s. Reports revealed that Notch is one of the most conserved developmental pathways involved in diverse biological processes such as the development, differentiation, survival and functions of many immune populations. Here, we provide an extended view of the pleiotropic effects of the Notch signaling on the innate lymphoid cell (ILC) biology. We review the current knowledge on Notch signaling in the regulation of ILC differentiation, plasticity and functions in diverse tissue types and at both the fetal and adult developmental stages. ILCs are early responder cells that secrete a large panel of cytokines after stimulation. By controlling the abundance of ILCs and the specificity of their release, the Notch pathway is also implicated in the regulation of their functions. The Notch pathway is therefore an important player in both ILC cell fate decision and ILC immune response.

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Tle4 Regulates Epigenetic Silencing of Gamma Interferon Expression during Effector T Helper Cell Tolerance

Cited by 11 publications

References 61 publications

The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

Methylene-tetrahydrofolate reductase contributes to allergic airway disease

The Notch signaling pathway involvement in innate lymphoid cell biology

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