The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program

Wu, Chuan; Chen, Zuojia; Dardalhon, Valérie; Xiao, Sheng; Thalhamer, Theresa; Liao, Mengyang; Madi, Asaf; Franca, Rafael Freitas Oliveira; Han, Timothy M.; Oukka, Mohammed; Kuchroo, Vijay K.

doi:10.1038/ni.3667

Cited by 49 publications

(34 citation statements)

References 50 publications

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“…Upon stimulation of naïve T cells in the presence of TCR triggering and TGF‐β, MSC is rapidly upregulated and participates to iTreg phenotype acquisition by suppressing the Th2 program. This occurs by physical interaction with GATA3 transcription factor, leading to its inactivation and thus to blockade of Th2 associated genes expression . Of note, very low levels of MSC expression were found in thymic Treg cells compared with that in iTreg cells, suggesting the involvement of a different molecular machinery in regulatory cell phenotype acquisition and maintenance.…”

Section: Resultsmentioning

confidence: 99%

Musculin inhibits human T‐helper 17 cell response to interleukin 2 by controlling STAT5B activity

et al. 2017

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We recently demonstrated that human T-helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study, we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the upregulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme. High PPP2R2B levels in human Th17 cells were responsible for the reduced STAT5B Ser-193 phosphorylation upon IL-2 signalling and, therefore, impaired STAT5B DNA binding and transcriptional activity on IL-2 target genes. PP2A, observed in Th17 cells, controls also STAT3, dephosphorylating Ser727, thus increasing its activity that plays a crucial role in Th17 development and/or maintenance. Thus, our findings identify an additional mechanism responsible for the limited expansion of human Th17 cells, and could provide a further explanation for the rarity of these cells in inflamed tissues.Keywords: IL-2 r Musculin r Proliferation r RORC r STAT5 r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Annunziato e-mail: francesco.annunziato@unifi.it IntroductionThe decision of a naïve CD4 + T-helper (Th) cell to acquire a particular effector phenotype is dictated by the cytokines produced by cells of the innate immunity in response to microbes and the consequent activation of transcription factors. In the presence of C 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1428 Veronica Santarlasci et al. Eur. J. Immunol. 2017. 47: 1427-1442 IL-12, naïve T cells activate signal transducer and activator of transcription 4 (STAT4) and T-bet, which induce the production of IFN-γ (Th1 cells); in the presence of IL-4, naïve T cells activate STAT6 and GATA-3, which stimulate the production of IL-4, IL-5, and IL-13 (Th2 cells); finally, in the presence of IL-1β and IL-23, naïve T cells activate STAT3 and retinoic acid orphan receptor (ROR)γt that allow them to produce IL-17 (Th17 cells). Th1 cells activate in turn macrophages, NK cells and B cells and play an important role in the protection against intracellular microbes, but they have also been thought to play a pathogenic role in autoimmune disorders. Th2 cells activate eosinophil granulocytes, mast cells, basophils, as well as the production of IgE by B cells, thus contributing to the protection against extracellular parasites, venoms and irritants, but they can also be responsible for atopic disorders. Th17 cells activate macrophages, B cells and also neutrophil granulocytes, thus favoring the protection against extracellular microbes. These cells seem to play an even more important pathogenic role than Th1 cells in autoimmune diseases [1]. However, despite their probably pow...

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Section: Resultsmentioning

confidence: 99%

Musculin inhibits human T‐helper 17 cell response to interleukin 2 by controlling STAT5B activity

et al. 2017

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“…In the well‐characterized model of IBD in Rag1 −/− mice, the infusion of CD4 + CD25 − CD45RB high effector T‐cells leads to the development of colitis, whereas Treg cells have been reported to be protective against the development of colitis (Bartczak et al ., ). Foxp3 is the master regulator of Treg cell development, and the deletion of the gene encoding Foxp3 results in multi‐organ tissue inflammation together with a loss of Treg cell function and an excessive generation of effector T‐cells, which leads to premature death in mice (Wu et al ., ). Du et al .…”

Section: Discussionmentioning

confidence: 97%

“…In the wellcharacterized model of IBD in Rag1 À/À mice, the infusion of CD4 + CD25 À CD45RB high effector T-cells leads to the development of colitis, whereas Treg cells have been reported to be protective against the development of colitis (Bartczak et al, 2017). Foxp3 is the master regulator of Treg cell development, and the deletion of the gene encoding Foxp3 results in multiorgan tissue inflammation together with a loss of Treg cell function and an excessive generation of effector T-cells, which leads to premature death in mice (Wu et al, 2017). Du et al (2013) found that p300 leads to dramatic effects on phenotypic changes in Treg cells, and they found the natural compound garcinol induces physical degradation of p300 through the lysosomal degradation processes, which could be used as a cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Cambogin suppresses dextran sulphate sodium‐induced colitis by enhancing Treg cell stability and function

Kim

Jiang

et al. 2018

British J Pharmacology

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Background and PurposeInflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract, and an impaired immune response plays a critical role in IBD. The current drugs and therapies for IBD treatment are of limited use, therefore, there is a need to find novel drugs or therapies for this disease. We investigated the effect of cambogin in a mouse model of dextran sulphate sodium (DSS)‐induced colitis and whether cambogin attenuates inflammation via a Treg‐cell‐mediated effect on the immune response.Experimental ApproachChronic colitis was established in mice using 2% DSS, and cambogin (10 mg·kg−1, p.o.) was administered for 10 days. Body weight, colon length and colon histology were assessed. Cytokine production was measured using elisa and quantitative real‐time PCR. To evaluate the mechanism of cambogin, human CD4+CD25hiCD127lo Treg cells were isolated from peripheral blood mononuclear cells. Major signalling profiles involved in Treg cell stability were measured.Key ResultsCambogin attenuated diarrhoea, colon shortening and colon histological injury and IL‐6, IFN‐γ and TNF‐α production in DSS‐treated mice. Cambogin also up‐regulated Treg cell numbers in both the spleen and mesenteric lymph nodes. Furthermore, cambogin (10 μM) prevented Foxp3 loss in human primary Treg cells in vitro, and promoted USP7‐mediated Foxp3 deubiquitination and increased Foxp3 protein expression in LPS‐treated cells.Conclusions and ImplicationsThe effect of cambogin on DSS‐induced colitis is expedited by a Treg‐cell‐mediated modification of the immune response, suggesting that cambogin could be applied as a novel agent for treating colitis and other Treg cell‐related diseases.

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“…In addition, Obata et al (2014) found that Uhrf1 facilitated colonic T reg cell proliferation to restrain colitis, while our data demonstrated that Uhrf1 inhibited iT reg cell differentiation to keep the identity of conventional T cells. Notably, increasing evidence suggested that the same factors might play distinct roles in different T reg cell subsets (Pabbisetty et al, 2014;Kitagawa et al, 2017;Wu et al, 2017;Ghosh et al, 2018). Colonic T reg cells and iT reg cells were generated in different locations and in response to different environmental signals (Zhou et al, 2009;Josefowicz et al, 2012;Arpaia et al, 2013;Furusawa et al, 2013;Luu et al, 2017), and a single-cell transcriptomics study showed that T reg cells generated from lymphoid organs and colon were quite heterogeneous, which might be due to their adaptation to the local environments (Miragaia et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity

Sun

Cui

Feng

et al. 2019

Journal of Experimental Medicine

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Regulatory T (T reg) cells are required for the maintenance of immune homeostasis. Both TGF-β signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-β signaling participates in the epigenetic regulation of Foxp3 remains largely unknown. Here we showed that T cell–specific ablation of Uhrf1 resulted in T reg–biased differentiation in TCR-stimulated naive T cells in the absence of TGF-β signaling, and these Foxp3+ T cells had a suppressive function. Adoptive transfer of Uhrf1−/− naive T cells could significantly suppress colitis due to increased iT reg cell generation. Mechanistically, Uhrf1 was induced upon TCR stimulation and participated in the maintenance of DNA methylation patterns of T reg cell–specific genes during cell division, while it was phosphorylated upon TGF-β stimulation and sequestered outside the nucleus, and ultimately underwent proteasome-dependent degradation. Collectively, our study reveals a novel epigenetic mechanism of TGF-β–mediated iT reg cell differentiation by modulating Uhrf1 activity and suggests that Uhrf1 may be a potential therapeutic target in inflammatory diseases for generating stable iT reg cells.

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The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program

Cited by 49 publications

References 50 publications

Musculin inhibits human T‐helper 17 cell response to interleukin 2 by controlling STAT5B activity

Musculin inhibits human T‐helper 17 cell response to interleukin 2 by controlling STAT5B activity

Cambogin suppresses dextran sulphate sodium‐induced colitis by enhancing Treg cell stability and function

TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity

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