The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1

Venuprasad, K.; Huang, Haining; Harada, Yohsuke; Elly, Chris; Subramaniam, Malayannan; Spelsberg, Thomas C.; Su, Jin; Liu, Yun‐Cai

doi:10.1038/ni1564

Cited by 162 publications

(205 citation statements)

References 42 publications

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“…S7), suggesting that they were induced T regs (iT regs ). Multiple recent reports have elucidated the molecular mechanisms leading to TGF-β-mediated Foxp3 induction in iT regs in a variety of disease settings (41,59,60). By using a Foxp3 reporter, our data support that TGF-β is required for T reg homing to mouse MBs.…”

Section: Discussionsupporting

confidence: 69%

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Gate

Danielpour

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8 + / killer cell lectin-like receptor G1 high (KLRG1 hi )/IL-7R lo short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.cancer immunology | neuroimmunology | neuro-oncology

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Section: Discussionsupporting

confidence: 69%

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Gate

Danielpour

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, a kinetic study of TGF-b1-induced Foxp3 expression showed a time delay between activation of Smad molecules (Smad2 and Smad3) and Foxp3 expression [19], implicating an additional indirect role of Smad on Foxp3 regulation or the importance of a Smad-independent pathway. To support this argument, Venuprasad et al [41] recently reported that TGF-b-inducible early gene-1 product acts as a transcriptional activator for the Foxp3 gene. Though the TGF-b1-induced Smadindependent pathway could be important, we show that its role is not as prominent as the Smad3-and Smad2-dependent direct and indirect pathways.…”

Section: Expression Was Enhanced In T Cells From P50mentioning

confidence: 91%

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

et al. 2009

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The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3 + Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-b1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-b1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-b1-induced-Treg generation from Smad3 À/À mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-jB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-b1 significantly attenuates NF-jB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-jB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-jB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-b1-induced-Treg cells for therapeutic purposes. There are reports documenting a reduction in the number or function of Treg cells in patients with numerous autoimmune diseases, including diabetes, rheumatoid arthritis, psoriasis, myasthenia gravis or sarcoidosis [12][13][14][15]. Thus, one possible way for restoration of self-tolerance in these patients could be by the infusion of Treg cells having an increased ability to control ongoing autoimmune destruction. Due to the limited availability of nTreg cells, in vitro generated iTreg cells may serve as an alternative source of Treg cells for therapeutic purposes. There is strong evidence that these Foxp3 + iTreg cells can prevent/delay the development of Type 1 Diabetes in the NOD mice [16,17]. Hence, the regulation of Foxp3 expression during iTreg generation is of considerable interest. Relatively little is known about the regulation of Foxp3 in the periphery. The essential roles of IL-2, TGF-b and TCR signaling in iTreg generation have been established [11,[18][19][20]. However, it is unclear which particular arms in each of these pathways are important in FoxP3 regulation. TGF-b1 is a pluripotent cytokine that has pronounced effects on T-cell-mediated immune suppression as well as on the control of autoimmunity. The binding of TGF-b1 to its receptor complex activates the intracellular kinase domain of TGF-bRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non-Smad proteins (Smad-independent pathway) [21]. After forming a heterodimer with phosphorylated Smad4, activated Smad2 and Smad3 translocate to the nucleus where they regulate TGF-b1-dependent gene expression. The generation of nTreg cells from the thymus of TGF...

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“…In accordance, Itch À/À Th2 cells are resistant to ionomycin-induced anergy as well as high doses of tolerizing antigen in a mouse model for asthmatic airway inflammation [51]. Moreover, Itch À/À CD4 1 T cells are resistant to T reg -dependent immunosuppression, and Itch À/À T reg cells differentiated in the presence of TGF-b have low expression of Foxp3 and are unable to suppress airway inflammation [52]. In this study, it was proposed that Itch participates in the TGF-b-mediated differentiation of T reg cells by ubiquitiylating and activating the transcription factor TIEG1, which in turn appears to bind to and transactivate the Foxp3 promoter.…”

Section: Itchmentioning

confidence: 86%

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1

Cited by 162 publications

References 42 publications

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

E3 ubiquitin ligases in T‐cell tolerance

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