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Transcription factor Foxo1 is essential for IL-9 induction in T helper cells

ABSTRACT: Interleukin 9 (IL-9) producing helper T (Th9) cells play a crucial role in allergic inflammation, autoimmunity, immunity to extracellular pathogens and anti-tumor immune response. In addition to Th9, Th2, Th17 and Foxp3+ Treg cells produce IL-9. Transcription factor that is critical for IL-9 induction in Th2, Th9 and Th17 cells has not been identified. Here we show that Foxo1, a forkhead family transcription factor, requires for IL-9 induction in Th9 and Th17 cells. We further show that inhibition of AKT enhances IL-9 induction in Th9 cells while it reciprocally regulates IL-9 and IL-17 in Th17 cells via Foxo1. Mechanistically, Foxo1 binds and transactivates IL-9 and IRF4 promoters in Th9, Th17 and iTregs. Furthermore, loss of Foxo1 attenuates IL-9 in mouse and human Th9 and Th17 cells, and ameliorates allergic inflammation in asthma. Our findings thus identify that Foxo1 is essential for IL-9 induction in Th9 and Th17 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE100634 | GEO | 2017/07/09

SECONDARY ACCESSION(S): PRJNA392330

REPOSITORIES: GEO

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EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Project description:Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

2021-06-15 | GSE163056 | GEO

Proteome analysis revealed the essential functions of protein phosphatase PP2A in the induction of Th9 cells

Project description:we performed proteome analysis of Th9 cells to understand the involvement of proteins that might be crucial for the anti-tumor functions of Th9 cells. Here we show for the first time a comprehensive proteomic analysis of murine Th0 and Th9 cells, which identified 1451 total proteins among which 1367 proteins were common. Further analysis revealed that 118 proteins were upregulated while 81 proteins were downregulated in Th9 cells. Pathway analysis suggested an abundance of phosphoproteins in the proteome of Th9 cells. Among upregulated phosphoproteins which showed to be involved in immune 34 system, Ppp2ca (catalytic subunit of protein phosphatase, PP2A) was found to be highly expressed in Th9 cells. Although the role of PP2A has been shown to regulate the differentiation and functions of Th1,Th2, Th17 and Tregs, its role in differentiation and functions of Th9 cells is not identified yet. Our results show for the first time that PP2A is required for the differentiation and anti-tumor functions of Th9 cells. PP2A inhibition leads to the suppression of IL-9 induction and the expression of key transcription factors of Th9 cells.

2021-09-09 | PXD019506 | Pride

Staphylococcus aureus-derived factors promote Th9 cell polarization and strongly enhance a transcriptional program associated with inflammation and allergy

Project description:T helper (Th) 9 cells, characterized by robust secretion of IL-9, have been increasingly associated with allergic disease. However, if and how Th9 cells are modulated by environmental stimuli remains poorly understood. In this study, we show that exposure of CD4 T-cells to Staphylococcus (S.) aureus-derived factors, including its toxins, potently enhances Th9 cell frequency and IL-9 secretion. Furthermore, S. aureus increases the expression of Th9-promoting factors at a transcriptional level, such as FOXO1, miR-155 and TNFRSF4. Addition of retinoic acid (RA) dampens the Th9 responses induced by S. aureus and substantially changes the transcriptional program induced by this bacterium, while also altering the expression of genes associated with allergic inflammation. Together, our results demonstrate a strong influence of microbial and dietary factors on Th9 cell polarization, which may be important in the context of allergy development and treatment.

2023-01-01 | GSE206288 | GEO

Cul5 regulates CD4+ T cell fate choice and allergic inflammation

Project description:Antigen encounter directs CD4+ T cells to differentiate into T-helper or -regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern -helper versus -regulatory fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells developed enhanced Th2 and Th9 inflammation and pathophysiological features of atopic asthma upon allergen exposure. Following T cell activation, Cul5 formed a complex with CIS and pJak1. Loss of Cul5 function resulted in reduced ubiquitylation and increased stability of pJak1, elevated STAT6 activity, and a reduced threshold for IL-4 receptor signaling. In keeping with this, Cul5-deficient T cells deviated from Treg to Th9 differentiation in low IL-4 conditions. These data support that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.

2022-06-09 | PXD028492 | Pride

Transcriptional profiling of human in vitro primed Th1, Th2, Th9 and Treg T cells

Project description:To test whether human in vitro primed Th9 cells recapitulate the core pathogenic Th2 cell phenotype, we differentiated naïve T cells into Th1 (IL-12), Th2 (IL-4), Th9 (IL-4+TGF-β), and iTreg (TGF-β). After 7 days transcriptomic profiling by bulk RNA-seq was performed.

2022-10-31 | E-MTAB-12199 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. Th9+IFNgamma and Th9 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36554 | biostudies-arrayexpress

A regulatory CD9+ B cell subset controls HDM-induced allergic airway inflammation

Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice

2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress

A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus

Project description:IL-5 is a key cytokine that plays an important role in the development of pathological conditions in chronic allergic inflammation. Identification of a strategy to inhibit IL-5 production is important for establishment of new therapies for allergic inflammation. We found that SH-2251, a novel thioamide-related compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the formation of the active histone modifications (H3K4me3, H3K9ac, H3K27ac) at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II and the induction of Th2 cell-specific intergenic transcription between the Rad50 and Il5 gene locus was also inhibited. Furthermore, Th2 cell-driven airway inflammation in mice was suppressed by oral administration of SH-2251. We identified Gfi1 as a downstream target molecule of SH-2251 treatment. The expression of Gfi1 was dramatically decreased in SH-2251-treated Th2 cells. SH-2251-mediated inhibition of the IL-5-producing Th2 cell generation was restored by transduction of Gfi1. Thus, our study unearths SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits IL-5 production. Gene expression in SH-2251-treated and untreated Th2 cells

2013-04-30 | E-GEOD-42131 | biostudies-arrayexpress

DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α

Project description:Dual-specificity phosphatase 8 is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO) mice, mass spectrometry analysis, chromatin-immunoprecipitation sequencing, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, IL-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-DUSP8 cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of IL-9 mRNA levels in T cells and allergic responses of T-DUSP8 cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8–Pur-α interaction were indeed increased in the cytoplasm of T cells from human asthma patients and atopic dermatitis patients. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

2023-09-30 | PXD044818 | Pride

DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α

2023-09-30 | PXD044824 | Pride

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