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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206288 | GEO | 2023/01/01

REPOSITORIES: GEO

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The transcription factor BATF3 regulates the differentiation of TH9 cells and TH9-driven mucosal pathologies

Project description:T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3-/- TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role of BATF3 in TH9-induced mucosal inflammation.

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Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression

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2014-02-20 | E-GEOD-41317 | 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

TL1A signaling enhances the differentiation of TH9 cells and TH9-driven mucosal pathologies via BATF and BATF3 signaling pathways

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2019-01-08 | GSE60362 | GEO

Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology

Project description:T helper (Th) differentiation is regulated by diverse inputs including the Vitamin A metabolite retinoic acid (RA). RA acts through its receptor RAR to repress transcription of inflammatory cytokines, but it is also essential for Th-mediated immunity, pointing to complex effects of RA in Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during differentiation of CD4+ T cells to multiple Th subsets. RA effects were subset-selective, and quantitatively greatest in Th9 cells. RA globally antagonized Th9-promoting transcription factors (TFs) and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARa. RA-RARaactivity limited Th9-associated pulmonary inflammation in mice, and allergic inflammation in humans was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARa signaling in Th differentiation, arguing for a role for RA in IL-9 related diseases.

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Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression

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2017-02-06 | GSE86542 | GEO

Genome-wide maps of Super-enhancers in TH9 cells by H3K27Ac and BRD4 CHIP-Seq.

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2018-01-11 | GSE102940 | GEO

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

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